Search

To summarise the prognostic value of patient‐reported outcomes (PROs) in advanced gastro‐oesophageal (GO) cancer. We systematically searched multiple databases using search terms related to advanced GO cancer, PRO and prognosis. Studies examining the relationship between baseline PROs and prognosis were included. Two reviewers independently screened articles and extracted data on study design, survival and associations between PROs and survival, in both univariable and multivariable analyses. QUIPS was used for quality assessment. From 3004 studies screened, seven studies were eligible, comprising PRO data from 2761 of 3408 (81%) participants. Median survival times ranged from 4.5 to 9.5 months. Among participants with oesophageal squamous cell carcinoma (SCC), physical functioning, social functioning and fatigue (QLQ‐C30) were associated with overall survival (OS) in one univariable analysis. Among three studies of participants with adenocarcinoma, univariable analyses revealed associations between OS and global quality of life (QOL), physical functioning, role functioning and social functioning; two studies showed association with pain. There was an association between emotional functioning, fatigue, lack of mobility, lack of self‐care, appetite loss/anorexia and OS in one study. One multivariable analysis among participants with oesophageal SCC showed physical and social functioning was associated with OS. Among participants with adenocarcinoma, multivariable analyses showed associations between OS and physical functioning/lack of mobility, appetite loss/anorexia (three studies), global QOL, role functioning/lack of self‐care, pain (two studies) and social functioning (one study). Physical functioning, role functioning, social functioning, pain, anorexia and global QOL were associated with OS in advanced GO cancer. [ABSTRACT FROM AUTHOR]

Cancer research has led to remarkable advances in our understanding of cancer biology and strategies for prevention, screening and early detection, treatment, and survivorship care, resulting in declines in cancer mortality rates ([1]). Google Scholar Crossref Search ADS PubMed WorldCat 65 Richman I, Tessier-Sherman B, Galusha D, Oladele CR, Wang K. Breast cancer screening during the COVID-19 pandemic: moving from disparities to health equity. Google Scholar Crossref Search ADS PubMed WorldCat 32 Haghighat S, Jiang C, El-Rifai W, Zaika A, Goldberg DS, Kumar S. Urgent need to mitigate disparities in federal funding for cancer research. [Extracted from the article]

Purpose: Activity estimates should be accurately evaluated in phase 2 clinical trials to ensure appropriate decisions about proceeding to phase 3 trials. RECIST v1.1. progression-free survival (PFS) is a common endpoint in oncology; however, it can be influenced by assessment criteria and trial design. We assessed the value of central adjudication of investigator-assessed PFS times of participants in a double-blind, randomised phase 2 trial evaluating regorafenib versus placebo in advanced gastro-oesophageal cancer (AGITG INTEGRATE) to inform plans for central review in future trials. Methods: We calculated the proportion of participants with a disagreement between the site investigator assessment and blinded independent central review and in whom central review resulted in a change, then evaluated the effect of central review on study conclusions by comparing hazard ratios (HRs) for PFS based on site review versus central review. Post-progression unblinding was assessed with similar methods. Simulation studies explored the effect of differential and non-differential measurement error on treatment effect estimation and study power. Results: Disagreements between site assessments versus central review occurred in 8/147 (5.4%) participants, 5 resulting in amended date of progression (3.4%). PFS HRs (sites vs central review progression dates) were similar (0.39 vs 0.40). RECIST progression occurred in 82/86 (95%) of cases where post-progression unblinding was requested by the site investigator. Conclusions: Blinded independent central review was feasible and supported the reliability of site assessments, trial results, and conclusions. Modelling showed that when treatment effects were large and outcome assessments blinded, central review was unlikely to affect conclusions. [ABSTRACT FROM AUTHOR]

The article focuses on a study related to the hormone therapy used for the treatment of localized prostate cancer (PCa). Comparative study for intermittent androgen deprivation (IAD) therapy and continuous androgen deprivation (CAD) therapy is also discussed in the article. It also concludes that in men with increasing prostate specific antigen levels after definitive radiotherapy, intermittent androgen deprivation therapy did not differ from continuous androgen deprivation.

The article focuses on a study which describes that taxane plus anthracycline reduces mortality from early breast cancer. It informs that taxane-plus-anthracycline-based regimens or anthracycline-based regimens reduce breast cancer mortality rates in women by about one third irrespective of their age, estrogen receptor status and the use of endocrine therapy.

The article presents information on PEARLS (Presentations of Evidence Abstracted from Research Literature to Solve real peoples' problems) designed specially for medical students. These students include those who were starting clinical attachments in the third year of a 4-year program and who had already been taught the principles and basic skills of evidence-based medicine (EBM) during their first 2 years.

Simple Summary: Until recently the outcome for women with advanced endometrial carcinoma has been poor. New immune therapies have resulted in much better outcomes for some, but not all, women with advanced disease. Determining which women are likely to respond is important, both to identify potential responders and prevent overtreatment of women who are not likely to respond. In this study we looked to see if there were any other markers that could be used to better predict those tumors that would be more likely to respond to the immune therapy known as durvalumab versus those tumors more likely to be resistant. Using statistical methods to evaluate each of the components examined we determined the cut-off point with the best performance. We found that the presence of tumor associated inflammatory cells had the strongest association with response. We also found that an algorithm derived from our best performing cut-off points identified women not likely to respond to treatment. While the presence of inflammatory cells was not significant when mismatch repair status was considered, our novel algorithm was. This is a small study and the findings do require validation in a larger group of women. Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed. [ABSTRACT FROM AUTHOR]

This research investigates why a beneficial treatment effect reported at the first interim analysis (IA) may diminish at a subsequent analysis (SA). We examined three challenges in interpreting treatment effects from randomized clinical trials (RCTs) after the first positive IA: overestimation bias; non-proportional hazards; and heterogeneity in recruitment. We investigate how a penalized estimation method can address overestimation bias, and discuss additional factors to consider when interpreting positive IA results. We identified oncology RCTs reporting positive results at the initial IA and a SA for event-free (EFS) and overall survival (OS). We modeled: (1) the hazard ratio at IA (HR IA) versus its timing as measured by the information fraction (IF; i.e., events at IA versus total events sought); and (2), the ratio of HR IA to HR SA (rHR) versus the IF. This was repeated for HR IA adjusted for overestimation bias. Examples of the other two challenges were sought. Amongst 71 RCTs, HR IA were positively associated with the IF (slope: EFS 0.83, 95 % CI 0.44–1.22; OS 0.25, 95 % CI 0.10–0.41). HR IA tended to exaggerate HR SA , and more so the lower the IF (slope rHR versus IF: EFS 0.10, 95 % CI − 0.22 to 0.42; OS 0.26, 95 % CI 0.07–0.46). Adjusted HR IA did not exaggerate HR SA (slope rHR versus IF: EFS − 0.14, 95 % CI − 0.67 to 0.39; OS 0.02, 95 % CI − 0.26 to 0.30). Examples of two other challenges are shown. Overestimation bias, non-proportional hazards, and heterogeneity in recruitment and other important treatments should be considered when communicating estimates of treatment effects from positive IAs. • Estimates from positive first interim analyses may overestimate treatment effects. • A penalized maximum likelihood estimator may correct this overestimation bias. • Follow-up post-interim analysis allows accurate assessment of the treatment effect. [ABSTRACT FROM AUTHOR]

Objective: Palliative care improves outcomes for patients with thoracic cancer; however, limited evidence exists for the benefits of this approach for caregivers. This study aimed to advance understanding of the experiences of palliative care described by bereaved caregivers. Methods: Fifteen adult caregivers completed semi‐structured interviews following prior participation in a randomised controlled trial of early referral to palliative care versus discretionary referral to palliative care. Interviews explored caregiver experiences of palliative care delivery. Interview transcripts were thematically analysed. Results: Four related themes about the experiences of palliative care were identified, each of which required sufficient time between palliative care first contact and death: 'relationship building'; 'clear communication and information'; 'access to practical support'; and 'access to psychosocial support'. The core category underpinning these themes was palliative care facilitates caregiver preparedness. Caregivers noted that palliative care played a critical role in preparing them for the future and described a sense of practical and emotional 'relief' associated with the support services made available to them. Conclusion: Our findings emphasise that palliative care can have a positive impact on caregivers' preparedness for providing the care needed by thoracic cancer patients and that this can improve the experiences of both caregivers and patients. [ABSTRACT FROM AUTHOR]

Background: Previously, results from the TheraP trial showed that treatment with lutetium-177 [177Lu]Lu-PSMA-617 improved frequency of prostate-specific antigen (PSA) response rate and progression-free survival compared with cabazitaxel in men with metastatic castration-resistant prostate cancer. In this study, we aimed to analyse gallium-68 [68Ga]Ga-PSMA-11 PET (PSMA-PET) and 2-[18F]fluoro-2-deoxy-D-glucose PET (FDG-PET) imaging parameters as predictive and prognostic biomarkers in this patient population.Methods: TheraP was a multicentre, open-label, randomised phase 2 trial that recruited men with metastatic castration-resistant prostate cancer after treatment with docetaxel who were suitable for cabazitaxel from 11 hospitals in Australia. Participants were required to be 18 years old or older; have adequate haematological, renal, and liver function; and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned (1:1) using a centralised system using minimisation with a random component and that stratified patients by disease burden, previous treatment with enzalutamide or abiraterone, and study site. Patients were either given cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles) or [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles). The primary study endpoint, analysed previously, was PSA response rate. The prespecified tertiary study endpoint was association between total tumour quantitative parameters on PSMA-PET, FDG-PET, and baseline characteristics with clinical outcomes. A SUVmean of 10 or higher on PSMA-PET was evaluated as a predictive biomarker for response to [177Lu]Lu-PSMA-617 versus cabazitaxel. A metabolic tumour volume (MTV) of 200 mL or higher on FDG-PET was tested as a prognostic biomarker. Both cutoff points were prespecified. The analysis was intention-to-treat, using logistic regression. This trial is registered with ClinicalTrials.gov, NCT03392428.Findings: 200 patients were randomly assigned between Feb 6, 2018, and Sept 3, 2019. 101 men were assigned to the cabazitaxel group and 99 were assigned to the [177Lu]Lu-PSMA-617 group. The median follow-up at data cutoff of July 20, 2020, was 18·4 months (IQR 12·8-21·8). 35 (35%) of 99 men who were assigned [177Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel had high PSMA uptake (SUVmean of ≥10). Odds of PSA response to [177Lu]Lu-PSMA-617 versus cabazitaxel were significantly higher for men with SUVmean of 10 or higher compared with those with SUVmean of less than 10 (odds ratio [OR] 12·19 [95% CI 3·42-58·76] vs 2·22 [1·11-4·51]; padj=0·039 for treatment-by-SUVmean interaction). PSA response rate for [177Lu]Lu-PSMA-617 compared with cabazitaxel was 32 (91% [95% CI 76-98]) of 35 men versus 14 (47% [29-65]) of 30 men in patients with SUVmean of 10 or higher, and 33 (52% [39-64]) of 64 men versus 23 (32% [22-45]) of 71 men in those with SUVmean of less than 10. High-volume disease on FDG-PET (MTV ≥200 mL) was seen in 30 (30%) of 99 men who were assigned [177Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel. PSA response rate for both treatment groups combined for FDG-PET MTV of 200 mL or higher versus FDG-PET MTV of less than 200 mL was 23 (38% [95% CI 26-52]) of 60 men versus 79 (56% [48-65]) of 140 men (OR 0·44, 95% CI 0·23-0·84; padj=0·035).Interpretation: In men with metastatic castration-resistant prostate cancer, PSMA-PET SUVmean was predictive of higher likelihood of favourable response to [177Lu]Lu-PSMA-617 than cabazitaxel, which provides guidance for optimal [177Lu]Lu-PSMA-617 use. High FDG-PET MTV was associated with lower responses regardless of randomly assigned treatment, warranting further research for treatment intensification. A strength of this analysis is the validation of pre-specified cutpoints within a multicentre, randomised, controlled trial. Quantitative PET parameters used, however, require specialised software and are not yet routinely available in most clinics.Funding: Prostate Cancer Foundation of Australia, Endocyte (a Novartis Company), Australian Nuclear Science and Technology Organisation, Movember Foundation, It's a Bloke Thing, CAN4CANCER, The Distinguished Gentleman's Ride. [ABSTRACT FROM AUTHOR]

Simple Summary: Men with metastatic castration-resistant prostate cancer (mCRPC) have shorter overall survival and resist therapy faster if their blood have a poor lipid profile. This poor lipid profile includes high levels of sphingolipids, thus reducing these sphingolipids may slow prostate cancer growth. The aim of our study is to determine if simvastatin can change a poor lipid profile (high sphingolipids) into a better profile (low sphingolipids) in mCRPC. Twenty-seven men with mCRPC were given simvastatin together with their standard treatment for 12 weeks. We found that 11 men had the poor lipid profile at the start of the study. After 12 weeks of treatment, 40% of these 11 men no longer had the poor lipid profile and their sphingolipids were reduced, regardless of changes in their blood cholesterol, LDL or triglycerides. In conclusion, simvastatin can modify the poor lipid profile in some men with mCRPC. Elevated circulating sphingolipids are associated with shorter overall survival and therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC), suggesting that perturbations in sphingolipid metabolism promotes prostate cancer growth. This study assessed whether addition of simvastatin to standard treatment for mCRPC can modify a poor prognostic circulating lipidomic profile represented by a validated 3-lipid signature (3LS). Men with mCRPC (n = 27) who were not on a lipid-lowering agent, were given simvastatin for 12 weeks (40 mg orally, once daily) with commencement of standard treatment. Lipidomic profiling was performed on their plasma sampled at baseline and after 12 weeks of treatment. Only 11 men had the poor prognostic 3LS at baseline, of whom five (45%) did not retain the 3LS after simvastatin treatment (expected conversion rate with standard treatment = 19%). At baseline, the plasma profiles of men with the 3LS displayed higher levels (p < 0.05) of sphingolipids (ceramides, hexosylceramides and sphingomyelins) than those of men without the 3LS. These plasma sphingolipids were reduced after statin treatment in men who lost the 3LS (mean decrease: 23–52%, p < 0.05), but not in men with persistent 3LS, and were independent of changes to plasma cholesterol, LDL-C or triacylglycerol. In conclusion, simvastatin in addition to standard treatment can modify the poor prognostic circulating lipidomic profile in mCRPC into a more favourable profile at twice the expected conversion rate. [ABSTRACT FROM AUTHOR]

Background: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC.Methods: We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models.Results: The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies.Conclusions: Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies. [ABSTRACT FROM AUTHOR]

Background: Optimising the care of individuals with cancer without imposing significant financial burden related to their anticancer treatment is becoming increasingly difficult. The American Society of Clinical Oncology (ASCO) has recommended clinicians discuss costs of cancer care with patients to enhance shared decision-making. We sought information to guide oncologists' discussions with patients about these costs.Methods: We searched Medline, EMBASE and clinical practice guideline databases from January 2009 to 1 June 2019 for recommendations about discussing the costs of care and financial burden. Guideline quality was assessed with the AGREE-II instrument.Results: Twenty-seven guidelines met our eligibility criteria, including 16 from ASCO (59%). 21 of 27 (78%) guidelines included recommendations about discussion or consideration of treatment costs when prescribing, with information about actual costs in four (15%). Recognition of the risk of financial burden or financial toxicity was described in 81% (22/27) of guidelines. However, only nine guidelines (33%) included information about managing the financial burden.Conclusions: Current clinical practice guidelines have little information to guide physician-patient discussions about costs of anticancer treatment and management of financial burden. This limits patients' ability to control costs of treatment, and for the healthcare team to reduce the incidence and severity of financial burden. Current guidelines recommend clinician awareness of price variability and high costs of treatment. Clinicians are recommended to explore cost concerns and address financial worries, especially in high risk groups. Future guidelines should include advice on facilitating cost transparency discussions, with provision of cost information and resources. [ABSTRACT FROM AUTHOR]

Background: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma.Methods: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415.Findings: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment.Interpretation: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial.Funding: AstraZeneca. [ABSTRACT FROM AUTHOR]

Purpose: The primary objective of this study was to determine the recommended dose of the vascular disrupting agent, BNC105P, in combination with gemcitabine and carboplatin in patients with ovarian cancer in first or second relapse with a minimum 4 month progression-free interval after last platinum.Methods: Patients received carboplatin AUC4 on day 1 in combination with escalating doses of 800 or 1000 mg/m2 gemcitabine on days 1 and 8 and escalating doses of 12 or 16 mg/m2 BNC105P on days 2 and 9 every 21 days for a maximum for six cycles. Maintenance treatment with 16 mg/m2 BNC105P treatment continued for a maximum of six additional cycles. Patients were followed for safety and anti-tumor activity.Results: Fifteen patients were enrolled in the study. Adverse events were most commonly of hematological origin. Dose-limiting toxicities (thrombocytopenia and neutropenia) occurred in two patients at the dose level of 800 mg/m2 gemcitabine, carboplatin AUC4 and 16 mg/m2 BNC105P. No dose-limiting toxicities were observed at a dose level of gemcitabine 1000 mg/m2, carboplatin AUC4 and BNC105P 12 mg/m2. BNC105P as a single agent was well tolerated at a dose of 16 mg/m2 in maintenance treatment. Ten patients (67%) achieved a complete or partial response according to CA125 and/or RECIST response criteria, four of 13 (31%) responded by RECIST alone. The median progression-free survival was 5.9 months.Conclusions: We have established that BNC105P 12 mg/m2 with gemcitabine 1000 mg/m2 and carboplatin AUC4 is the recommended dose level and has an acceptable toxicity profile. Further exploration of BNC105P in the ovarian cancer setting is planned. [ABSTRACT FROM AUTHOR]

Background Modified Glasgow Prognostic Score (mGPS) is predictive of survival in many advanced cancers, but has not been evaluated in recurrent ovarian cancer (ROC). The aim was to determine validity of mGPS in ROC, investigate its associations with health related quality of life (HRQL) and ECOG performance status (PS). Methods mGPS is based on serum C reactive protein (CRP) and albumin, with scores ranging from 0 (least) to 2 (most). HRQL was measured with EORTC QLQ C-30 and OV-28. χ 2 tests for trend were used to examine the relationship between HRQL, PS and mGPS. Cox proportional hazards regression was used to assess associations between mGPS, HRQL, clinicopathological factors, and overall survival (OS). Results Inflammatory markers were available in 516 of 948 patients in GCIG SBS. 200(39%) had potentially platinum sensitive ROC with ≥ 3 lines of chemotherapy, 316(61%) had platinum resistant ROC. 282(55%), 123(24%), 111(22%) had mGPS of 0, 1, 2, respectively. Median OS (months) was 18.1, 9.6, and 6.6 for mGPS 0, 1, and 2 respectively. mGPS was an independent predictor of OS after adjusting for PS and platinum sensitivity (p < 0.001). mGPS remained a predictor of OS after adjusting for physical function, role function, global health status, abdominal/GI symptoms, and multiple clinicopathologic factors (p = 0.02). Worse PS and higher mGPS were associated with poorer HRQL (p < 0.001). Higher mGPS was associated with worse HRQL, independent of PS. Conclusion The mGPS is an independent predictor of OS in ROC after adjusting for HRQL and clinicopathological factors. Higher mGPS is associated with worse HRQL independent of PS. mGPS is simple, inexpensive and may be suitable for clinical practice, clinical trial patient selection and stratification. [ABSTRACT FROM AUTHOR]

Clinical trials to establish the efficacy of new agents in the adjuvant cancer setting typically take many years to complete. During that time, external factors can impact recruitment and reporting plans. An example is a new standard of care becoming available during the recruitment period. In this paper we describe how we modified the design of the RAMPART trial (NCT03288532) which was set up to investigate immune checkpoint inhibitor therapy in the adjuvant renal cancer setting. The trial had been initiated when no globally accepted adjuvant strategy after nephrectomy existed. A subsequent change in the standard of care for many patients with early renal cancer meant it was no longer feasible to continue to recruit. We needed to find a way to maximise the contribution that RAMPART participants could make to the evidence base for immune checkpoint inhibitor therapy without introducing bias or detriment to the integrity of the trial results. We describe how we agreed and incorporated all design and timeline changes while remaining blinded to accumulating data within the trial, thus protecting the reliability of the future results. We share details of our design modifications to guide others who may have similar experiences, particularly as more agents and combinations of agents are developed and investigated in similar adjuvant settings., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer., Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression., Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION., Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel., Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods., Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel., Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Background: Primary hypogonadism is a recognised complication in survivors of testicular cancer. However, secondary hypogonadism can result from other causes that suppress the hypothalamic-pituitary axis, including obesity, high dose glucocorticoids, chronic end organ failure, and diabetes. The aim of this study was to explore low total serum testosterone in Australian survivors of testicular cancer and examine associations with body mass index, age, and prior chemotherapy use., Methods: Clinical data including height, weight, diagnosis, treatment, and hormonal evaluations during follow-up were extracted from the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Chemocog study (2007-2012), accompanied by data from two Australian, high-volume testicular cancer centres included in the iTestis testicular cancer registry (2012-2019). Low testosterone was defined by a serum concentration of testosterone (T) < 10 nmol/L, and was classified as primary by a serum concentration of luteinising hormone (LH) > 8 IU/L, otherwise as secondary., Results: Two hundred eighty-five individuals with either stage 1 or advanced testicular cancer were included. Of these, 105 (37%) were treated with orchidectomy and chemotherapy. Forty-nine (17%) met criteria for low testosterone during follow-up: 21 (43%) had primary and 27 (55%) had secondary low testosterone. Survivors of testicular cancer with higher body mass index were more likely to display low testosterone, both primary (p = 0.032) and secondary (p = 0.028). Our data did not show evidence of an association between older age or chemotherapy use and low testosterone in our cohort., Conclusions: Low total serum testosterone was common in survivors of testicular cancer, and associated with a higher body mass index prior to orchidectomy, suggesting that elevated body mass index may contribute to low testosterone in this population, and that body weight, diet, and exercise should be addressed in testicular cancer follow-up., (© 2024. The Author(s).)

Purpose: The aim of this randomized, placebo-controlled, two-stage, phase II/III trial was to determine the efficacy of an oral cannabis extract in adults with refractory nausea and/or vomiting during moderately or highly emetogenic, intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Here, we report results of the prespecified combined analysis including the initial phase II and subsequent phase III components., Patients and Methods: Study treatment consisted of oral capsules containing either tetrahydrocannabinol 2.5 mg plus cannabidiol 2.5 mg capsules (THC:CBD) or matching placebo, taken three times a day from days -1 to 5, in addition to guideline-consistent antiemetics. The primary measure of effect was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during hours 0-120 after the first cycle of chemotherapy on study (cycle A)., Results: We recruited 147 evaluable of a planned 250 participants from 2016 to 2022. Background antiemetic prophylaxis included a corticosteroid and 5-hydroxytryptamine antagonist in 97%, a neurokinin-1 antagonist in 80%, and olanzapine in 10%. THC:CBD compared with placebo improved the complete response rate from 8% to 24% (absolute difference 16%, 95% CI, 4 to 28, P = .01), with similar effects for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index-Emesis quality-of-life questionnaire. More frequent bothersome adverse events of special interest included sedation (18% v 7%), dizziness (10% v 0%), and transient anxiety (4% v 1%). There were no serious adverse events attributed to THC:CBD., Conclusion: THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, but was associated with additional adverse events. Drug availability, cultural attitudes, legal status, and preferences may affect implementation. Future analyses will evaluate the cost-effectiveness of THC:CBD.

Background: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC., Methods: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15., Results: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15., Conclusions: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC., (© 2024 The Authors. The Prostate published by Wiley Periodicals LLC.)

Background: Enzalutamide and lutetium-177 [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [ 177 Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer., Methods: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [ 68 Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [ 177 Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing., Findings: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [ 177 Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group., Interpretation: The addition of [ 177 Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer., Funding: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company)., Competing Interests: Declaration of interests LE reports research grant support (to their institution) from Novartis and Clarity Pharma; consulting fees for lectures or advisory boards from Astellas, Janssen, AstraZeneca, Clarity, Novartis, and Telix in the past 5 years; and philanthropic grant support from the Prostate Cancer Foundation, St Vincent's Clinic Research Foundation, and Curran Foundation. SSa reports grants from Novartis/AAA, AstraZeneca, Merck Sharp & Dohme, Genentech, Pfizer, Amgen, and Senhwa to their institution; and personal fees from AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb, and AstraZeneca to their institution, outside the submitted work. CG donated personal fees from Astellas, Janssen, AstraZeneca, Bristol Myers Squibb, Pfizer/EMD Serono, Ipsen, Astellas, and MSD, direct and complete, to a third party not-for-profit. CG declares consulting fees (unrelated to this work) from Novotech, Cadex Geonomics, and BCAL Diagnostics; and participation on an advisory board for Alloplex. MSH reports grants and receipt of equipment, materials, drugs, medical writing, gifts, or other services from the Prostate Cancer Foundation, National Health and Medical Research Council (NHRMC), Movember, US Department of Defense, Medical Research Future Fund, Bayer, Peter MacCallum Foundation, Isotopia, and the Australian Nuclear Science and Technology Organisation; consulting fees from Merck Sharp & Dohme and Novartis; honoraria from Janssen, Novartis, AstraZeneca, and Astellas; support for meetings from Merck Sharp & Dohme, Novartis, Janssen, AstraZeneca, and Astellas; leadership or fiduciary role in other board from Australian Friends of Sheba; and other financial or non-financial interests from Peter MacCallum Cancer Centre and the University of Melbourne. DAP reports personal fees from Ipsen and Eisai, all outside the submitted work. RJF reports institution funding and consulting fees from AIQ Solutions, outside the submitted work; and committee involvement in the Australasian Radiopharmaceutical Trials Network (unpaid). MRS reports grants to his institution from the Australian NHMRC, Cancer Australia, Astellas, Amgen, AstraZeneca, Bayer, Bionomics, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tilray, all outside the submitted work. IDD reports grants from the NHMRC, during the conduct of the study; and institutional payments to support prostate cancer trials from Pfizer, ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, and Merck Sharp & Dohme, outside the submitted work. IDD is unremunerated Chair of the ANZUP Cancer Trials Group and is supported in part by an Australian NHMRC Investigator Grant (grant number 2016274). AMJ reports consulting or advisory roles (to their institution) from Janssen Oncology, Pfizer, and Astellas Pharma; and research funding (to their institution) from Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, Lilly, Pfizer, and AstraZeneca. AW declares consulting fees from MSD, Eisai, Bristol Myers Squibb, and Astellas; honoraria from Eisai and MSD; and participation on an advisory board from Loxo-Lilly, MSD, and Astellas. DP declares support for travel from Astellas and participation on an advisory board from Astellas. MC reports advisory board fees from Astellas. MV reports personal fees from AstraZeneca and MSD. AYZ reports grants or contracts from Astellas, Amgen, AstraZeneca, Bionomics, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tilray; consulting fees from Merck Sharpe & Dohme; honoraria from Merck Sharpe & Dohme, Astellas, Bayer, Pfizer, Merck, Mundipharma, Janssen, and AstraZeneca; and participation on a data safety monitoring board or advisory board from Merck, Merck Sharpe & Dohme, Astellas, and Bayer. JCG reports consulting fees from Bristol Myers Squibb, GlaxoSmithKline, and MSD; honoraria from Bayer, Ipsen, Eisai, Janssen, GlaxoSmithKline, and MSD; support to attend meetings from Bayer and BeiGene; and participation on a data safety monitoring board or advisory board from AstraZeneca. LH reports support for the present manuscript from Astellas; research funding from Astellas, Bayer, and Imagion; participation on advisory boards from Astellas, Bayer, Janssen, and MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Bayer, Janssen, and MSD; support for attending meetings from Bayer; a provisional patent (Australian number 2022902527, Prognostic Markers [plasma lipid prognostic signature in metastatic prostate cancer]; patent owned by the Chris O'Brien Lifehouse [their institution]); participation on a data safety monitoring board or advisory board from Astellas, Bayer, and Imagion; advisory board leadership role for ANZUP; and stock or stock options from Connected Medical Solutions. SY reports grants or contracts from NHMRC, Cancer Australia, Astellas, Amgen, AstraZeneca, Bionomics, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, and Tilray; and support for attending meetings from Bayer. All other authors declare no competing interests., (Copyright © 2024. Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Prognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [ 177 Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [ 177 Lu]Lu-PSMA compared with standard chemotherapy has not been established., Objective: To determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective)., Design, Setting, and Participants: All 200 patients were randomised in the TheraP trial to receive [ 177 Lu]Lu-PSMA-617 (n = 99) or cabazitaxel (n = 101) between February 2018 and September 2019., Outcome Measurements and Statistical Analysis: Predictive performance was investigated by testing whether the association between the modelled outcome classifications (favourable vs unfavourable outcome) was different for patients randomised to [ 177 Lu]Lu-PSMA versus cabazitaxel. The clinical benefit of the PSA50 model was evaluated using a decision curve analysis., Results and Limitations: The probability of PSA50 in patients classified as having a favourable outcome was greater in the [ 177 Lu]Lu-PSMA-617 group than in the cabazitaxel group (odds ratio 6.36 [95% confidence interval {CI} 1.69-30.80] vs 0.96 [95% CI 0.32-3.05]; p = 0.038 for treatment-by-model interaction). The PSA50 rate in patients with a favourable outcome for [ 177 Lu]Lu-PSMA-617 versus cabazitaxel was 62/88 (70%) versus 31/85 (36%). The decision curve analysis indicated that the use of the PSA50 model had a clinical net benefit when the probability of a PSA response was ≥30%. The predictive performance of the models for PSA PFS and OS was not established (treatment-by-model interaction: p = 0.36 and p = 0.41, respectively)., Conclusions: A previously developed outcome classification model for PSA50 was demonstrated to be both predictive and prognostic for the outcome after [ 177 Lu]Lu-PSMA-617 versus cabazitaxel, while the PSA PFS and OS models had purely prognostic value. The models may aid clinicians in defining strategies for patients with metastatic castration-resistant prostate cancer who failed first-line chemotherapy and are eligible for [ 177 Lu]Lu-PSMA-617 and cabazitaxel., Patient Summary: In this report, we validated previously developed statistical models that can predict a response to Lu-PSMA radioligand therapy in patients with advanced prostate cancer. We found that the statistical models can predict patient survival, and aid in determining whether Lu-PSMA therapy or cabazitaxel yields a higher probability to achieve a serum prostate-specific antigen response., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies., (© 2024. The Author(s).)

Background: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [ 177 Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [ 68 Ga]Ga-PSMA-11 and 2-[ 18 F]fluoro-2-deoxy-D-glucose (2-[ 18 F]FDG) PET-CT., Methods: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [ 68 Ga]Ga-PSMA-11 and 2-[ 18 F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[ 18 F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [ 177 Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m 2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete., Findings: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [ 177 Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [ 177 Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [ 177 Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [ 177 Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [ 68 Ga]Ga-PSMA-11 and 2-[ 18 F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1)., Interpretation: These results support the use of [ 177 Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[ 18 F]FDG-discordant disease., Funding: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride., Competing Interests: Declaration of interests MSH reports research grant support (to their institution) from Novartis (including AAA and Endocyte), Australian Nuclear Science and Technology Organization (ANSTO), Bayer, Isotopia, and MIM; and consulting fees for lectures or advisory boards from Astellas and AstraZeneca in the past 2 years, and from Janssen, MSD, and Mundipharma in the past 5 years. LE reports personal fees from AstraZenca, Janssen, and Astellas, outside the submitted work. SS reports grants from AAA, AstraZeneca, MSD, and Genetech to their institution; and personal fees from AstraZeneca, MSD, Bristol Myers Squibb, and AstraZeneca to their institution, outside the submitted work. DAP reports personal fees from Ipsen and Eisai, outside the submitted work. RJF reports institution funding and consulting fees from AIQ Solutions, outside of the submitted work; and committee involvement in the Australasian Radiopharmaceutical Trials Network (unpaid). CG donated personal fees from Astellas, Janssen, AstraZeneca, Bristol Myers Squibb, EMD Serono, Ipsen, Astellas, and MSD, direct and complete, to a third party not-for-profit. AMS reports trial or research funding from EMD Serono, ITM, AVID, Medimmune, Telix, Adalta, Fusion, Antengene, Earli, Curis, and Cyclotek; grants from the Australian National Health and Medical Research Council (NHMRC) and Medical Research Future Fund (MRFF), including an NHMRC Investigator Grant; and board and advisory committee involvement for the Australian and New Zealand Society of Nuclear Medicine and Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group (unpaid); all outside the submitted work. EMK reports personal fees from Astellas Pharma, Janssen, Pfizer, Ipsen, and Roche, all outside the submitted work; and is supported by a Prostate Cancer Foundation Young Investigator Award and University of British Columbia Killam Postdoctoral Fellowship. AAA reports grants or personal fees from Janssen, Astellas, Novartis, Merck Serono, Tolmar, Amgen, Pfizer, Bayer, Telix Pharmaceuticals, Bristol Myers Squibb, Sanofi, Noxopharm, AstraZeneca, Ipsen, MSD, Aculeus Therapeutics, and Daiichi Sankyo; and grants from Astellas (investigator), Merck Serono (investigator), AstraZeneca (investigator), Bristol Myers Squibb (institutional), AstraZeneca (institutional), Aptevo Therapeutics (institutional), GlaxoSmithKline (institutional), Pfizer (institutional), MedImmune (institutional), Astellas (institutional), Synthorx (institutional), Bionomics (institutional), Sanofi Aventis (institutional), Novartis (institutional), Ipsen (institutional), Exelixis (institutional), MSD (institutional), Janssen (institutional), Eli Lilly (institutional), Gilead Sciences (institutional), Merck Serono (institutional), and Hinova (institutional), all outside the submitted work. MRS reports grants to his institution from the NHMRC, Cancer Australia, Astellas, Amgen, AstraZeneca, Bayer, Bionomics, Bristol Myers Squibb, Celgene, Medivation, MSD, Pfizer, Roche, Sanofi, and Tilray, all outside the submitted work. IDD reports grants from the NHMRC, during the conduct of the study; and institutional payments to support prostate cancer trials from Pfizer, the ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, and MSD, outside the submitted work. IDD is also unremunerated Chair of the ANZUP Cancer Trials Group, and is supported in part by an NHMRC Investigator Grant (grant number 2016274). AMJ reports consulting or advisory roles (to their institution) from Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Pfizer, Novartis, Bristol Myers Squibb, Merck Serono, Eisai, Bayer, and Astellas Pharma; and research funding (to their institution) from Bristol Myers Squibb, Janssen Oncology, MSD, Mayne Pharma, Genentech, Bayer, Lilly, Pfizer, and AstraZeneca. AI reports personal fees for a consulting role for Curium Pharma and payment to their institution for a consulting role from Ambrx Pharma, all outside the submitted work. AJW reports a consulting role for and travel support from Bayer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: International guidelines advocate for active surveillance as the preferred treatment strategy for patients with stage 1 testicular cancer after orchidectomy although a personalized discussion is required., Materials and Methods: We conducted an analysis of individuals registered in iTestis, Australia's testicular cancer registry, to describe the patterns of relapse and outcomes of patients treated in Australia where the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Surveillance Recommendations are widely adopted., Results: A total of 650 individuals diagnosed between 2000 and 2020 were included, 63% (411 of 650) seminoma and 37% (239 of 650) nonseminoma. The median age was 34 years (range 14-74). 26% (106 of 411) with seminoma and 15% (36 of 239) nonseminoma received adjuvant chemotherapy. After a median follow-up of 43 months (range 0-267) postorchidectomy, relapse occurred in 10% (43 of 411) of seminoma and 18% (43 of 239) of nonseminoma. The two-year relapse-free survival was 92% (95% CI, 89 to 95) and 82% (95% CI, 78 to 87) in seminoma and nonseminoma, respectively. All relapses (86 of 86) were detected at a routine surveillance visit; 98% (85 of 86) were asymptomatic and detected solely through imaging (62 of 86, 72%), tumor markers (6 of 86, 7%), or a combination (17 of 86, 20%). The most common relapse site was isolated retroperitoneal lymphadenopathy (53 of 86, 62%). No nonpulmonary visceral metastases occurred. At relapse, 98% (84 of 86) had International Germ Cell Cancer Collaborative Group (IGCCCG) good prognosis; 2 of 86 intermediate prognosis (both nonseminoma). No deaths occurred., Conclusion: In our cohort of stage 1 testicular cancer, where national surveillance recommendations have been widely adopted, recurrences were detected at routine surveillance visits and, almost exclusively, asymptomatic with IGCCCG good-prognosis disease. This provides reassurance that active surveillance is safe.

Background: To evaluate the claim that oncologists overestimate expected survival time (EST) in advanced cancer., Methods: We pooled 7 prospective studies in which observed survival time (OST) was compared with EST (median survival in a group of similar patients estimated at baseline by the treating oncologist). We hypothesized that EST would be well calibrated (approximately 50% of EST longer than OST) and imprecise (<30% of EST within 0.67 to 1.33 of OST), and that multiples of EST would provide well-calibrated scenarios for survival time: worst-case (approximately 10% of OST <1/4 of EST), typical (approximately 50% of OST within half to double EST), and best-case (approximately 10% of OST >3 times EST). Associations between baseline characteristics and calibration of EST were assessed., Results: Characteristics of 1,211 patients: median age 66 years, male 61%, primary site lung (40%) and upper gastrointestinal (16%). The median OST was 8 months, and EST was 9 months. Oncologists' estimates of EST were well calibrated (50% longer than OST) and imprecise (28% within 0.67 to 1.33 of OST). Scenarios for survival time based on simple multiples of EST were well calibrated: 8% of patients had an OST less than 1/4 their EST (worst-case), 56% had an OST within half to double their EST (typical), and 11% had an OST greater than 3 times their EST (best-case). Calibration was independent of age, sex, and cancer type., Conclusions: Oncologists were no more likely to overestimate survival time than to underestimate it. Simple multiples of EST provide well-calibrated estimates of worst-case, typical, and best-case scenarios for survival., (© The Author(s) 2023. Published by Oxford University Press.)

Objectives: This study aimed to quantify adult preferences for adjuvant immunotherapy for resected melanoma and the influence of varying levels of key attributes and baseline characteristics., Methods: A D-efficient design generated 12 choice tasks for two alternative treatments, adjuvant immunotherapy or no adjuvant immunotherapy. Recruitment to the online discrete choice experiment (DCE) occurred via survey dissemination by eight Australian melanoma consumer and professional groups, targeting adults with resected stage III melanoma, considering or having received adjuvant immunotherapy. The DCE included six attributes with two to three levels each, including 3-year risk of recurrence, mild, permanent and fatal adverse events (AEs), drug regimen and annual out-of-pocket costs. A mixed multinomial logit model was used to estimate preferences and calculate marginal rates of substitution and marginal willingness to pay (mWTP)., Results: The DCE was completed by 116 respondents, who chose adjuvant immunotherapy over no adjuvant immunotherapy in 70% of choice tasks. Respondents preferred adjuvant immunotherapy when associated with reduced: probabilities of recurrence, permanent and fatal AEs, and out-of-pocket costs. mWTP for an absolute reduction of 1% in 3-year risk of recurrence was less for respondents with lower rather than higher incomes, AU$794 (US$527) and AU$2190 (US$1454) per year. Respondents accepted an additional 4% chance of a permanent AE to reduce their absolute risk of 3-year recurrence by 1%. Respondents were willing to accept an extra 2% chance of 3-year recurrence to lower their chance of a fatal AE by 1%., Conclusions: Almost three-quarters of respondents chose adjuvant immunotherapy over no adjuvant immunotherapy, preferring treatment that improved efficacy and safety. Findings may inform decisions about access to adjuvant immunotherapy following surgery for melanoma., (© 2023. The Author(s).)

Background: Sentinel node-based management (SNBM) is the international standard of care for early breast cancer that is clinically node-negative based on randomised trials comparing it with axillary lymph node dissection (ALND) and reporting similar rates of axillary recurrence (AR) without distant disease. We report all ARs, overall survival, and breast cancer-specific survival at 10-years in SNAC1., Methods: 1.088 women with clinically node-negative, unifocal breast cancers 3 cm or less in diameter were randomly assigned to either SNBM with ALND if the sentinel node (SN) was positive, or to SN biopsy followed by ALND regardless of SN involvement., Results: First ARs were more frequent in those assigned SNBM rather than ALND (11 events, cumulative risk at 10-years 1·85%, 95% CI 0·95-3.27% versus 2 events, 0·37%, 95% CI 0·08-1·26%; HR 5·47, 95% CI 1·21-24·63; p = 0·013). Disease-free survival, breast cancer-specific survival, and overall survival were similar in those assigned SNBM versus ALND. Lymphovascular invasion was an independent predictor of AR (HR 6·6, 95% CI 2·25-19·36, p < 0·001)., Conclusion: First ARs were more frequent with SNBM than ALND in women with small, unifocal breast cancers when all first axillary events were considered. We recommend that studies of axillary treatment should report all ARs to give an accurate indication of treatment effects. The absolute frequency of AR was low in women meeting our eligibility criteria, and SNBM should remain the treatment of choice in this group. However, for those with higher-risk breast cancers, further study is needed because the estimated risk of AR might alter their choice of axillary surgery., Competing Interests: Declaration of competing interest ICreports grants from Australian National Health and Medical Research Council, grants from National Breast Cancer Foundation, grants from NZ Cancer Society, grants from Scottswood Trust, New Zealand, non-financial support from Astra Zeneca, during the conduct of the study; personal fees from Guerbet Australia Pty. MS reports grants from Astellas, grants from Amgen, grants from Astra Zeneca, grants from Bayer, grants from Bionomics, grants from Bristol-Myers Squibb, grants from Celgene, grants from Medivation, grants from Merck Sharp & Dohme, grants from Pfizer, grants from Roche, grants from Sanofi, grants from Tilray, outside the submitted work. RS reports grants from National Health and Medical Research Council (Australia), grants from Medical Research Future Fund (Australia), grants from Several Pharmaceutical Companies, outside the submitted work., (Copyright © 2023. Published by Elsevier Ltd.)

Patient-reported outcomes (PROs) provide a valid, standardized way of assessing symptoms, adverse events and the subjective benefit of treatment from the patient's perspective. Assessment of PROs is critical in ovarian cancer due to the high morbidity of the disease and its treatments. Several well-validated PRO measures are available to assess PROs in ovarian cancer. Their inclusion in clinical trials can provide evidence on the benefits and harms of new treatments based on patients' experiences to guide improvements in clinical practice and health policy. Aggregate PRO data collected in clinical trials can be used to inform patients about likely treatment impacts and assist them to make informed treatment decisions. In clinical practice, PRO assessments can facilitate monitoring of a patient's symptoms throughout treatment and follow-up to guide their clinical management; in this context, an individual patient's responses can facilitate communication with their treating clinician about troublesome symptoms and their impact on their quality of life. This literature review aimed to provide clinicians and researchers with a better understanding of why and how PROs can be incorporated into ovarian cancer clinical trials and routine clinical practice. We discuss the importance of assessing PROs throughout the ovarian cancer disease and treatment trajectory in both clinical trials and clinical practice, and provide examples from existing literature to illustrate the uses of PROs as the goals of treatment change in each setting., Competing Interests: Professor Martin R Stockler reports grants from AMGEN, grants from ASTELLAS, grants from AstraZeneca, grants from Bayer, grants from Beigene, grants from BMS, grants from Medivation, grants from MSD, grants from Novartis, grants from Pfizer, grants from Roche, grants from Sanofi, grants from Tilray, outside the submitted work. Professor Michael L Friedlander reports grants, personal fees, is a member of Advisory boards received fees for lectures and travel from ASTRA ZENECA, personal fees from MSD, personal fees from TAKEDA, personal fees from LILLY, personal fees from EISEI, is an Advisory Board-not compensated for INCYCLIX, personal fees from GSK, grants from Novartis, grants from BEIGENE, outside the submitted work; The authors report no other conflicts of interest in this work., (© 2023 Campbell et al.)

Background: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy., Methods: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m 2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m 2 ) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088., Findings: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths., Interpretation: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting., Funding: National Health and Medical Research Council and National Cancer Institute., Competing Interests: Declaration of interests LRM reports grant from National Health and Medical Research Council (NHMRC) Australia for support for the present manuscript. KNM reports research funding to institution outside of submitted work from PTC Therapeutics, Lilly, Merck, and GSK/Tesaro; participation on an Advisory Board for AstraZeneca, Aravive, Alkemeres, Addi, Blueprint Medicines, Eisai, EMD Serono, Elevar Therapeutics, GSK/Tesaro, Genentench/Roche, Hengrui, Immunogen, INXmed, IMab, Lilly, Mereo, Mersana Therapeutics, Merck, Myriad, Novartis, Novocure, OncXerna, Onconova Therapeutics, Tarveda Therapeutics, VBL Therapeutics, and Verastem Oncology; and leadership role as Associate Director of Gynecological Oncology Group Partners and on the Board of Directors for GOG Foundation. WSJ reports honoraria for invited talks from Carl Zeiss; payments made for participation on a data and safety monitoring board from Novocure; and Co-Chair of Gynaecological Committee until June 2020 with NRG Oncology. DKG reports grants and contracts from Elekta; payment or honoraria from ANZGOG, payment for expert testimony from in a Montana court case, participating on a DSMB or Advisory Board for Merck; and leadership role in NRG Oncology as Co-Chair of the Gyn Committee. PK reports funding outside of this submitted work from ANZGOG Fund for New Research and Medical Research Future Fund Reproductive Cancers Grant; is the Deputy Chair of Treatment Pillar for the National Cervical Cancer Elimination Strategy; is on the Board Director for ANZGOG and AMA Victoria. WKH reports consulting fee payments from AstraZeneca and SeaGen and payment for participation on a DSMB from Syneos and Inovio. CAM reports support for the present manuscript from National Cancer Institute, and funding to their institution from Syros, Deciphera, Astellas Pharma GlaxoSmithKline/Tesaro, Seagen, Genmab, EMD Serono, Merck, Regeneron, Moderna, Astra Zeneca, and Genentech, outside of the submitted work. TEL reports support for the present manuscript from the National Cancer Institute Community Research Program and support for attending meetings and travel from SHCC MU NCORP Grant. CHH reports support for the present manuscript from GOG and NRG, and leadership role in the Executive Board, Western Association of Gynecologic Oncology, and the 2023 Program Committee Chair, Western Association of Gynecologic Oncology. MQ reports personal payment as Chair of an independent data and safety monitoring committee for the Garnet Study and Tesaro Study from GSK, and Chair of DSMB for the COMPASS Study. DR reports trial funding all to institution outside of submitted work from MSD, GSK, Regeneron, Roche, Bristol Myers Squibb, Kura, ALX Oncology and participation on a DSMB for MSD, Regeneron, Sanofi. BJM reports consulting fees from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, and VBL Therapeutics, Verastem, Zentalis and payment or honoraria from AstraZeneca, Merck, Myriad, TESARO/GSK, Roche/Genentech, Clovis, and Easai. MRS reports grant to institution from NHMRC Australia for support for the present manuscript, and grants to their institution from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Tilray. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: 177 LuPSMA is an effective treatment in metastatic castrate-resistant prostate cancer with trials adopting a standardised dose interval. Adjusting treatment intervals utilising early response biomarkers may improve patient outcomes., Objective: This study evaluated progression-free survival (PFS) and overall survival (OS) based on treatment interval adjustment utilising 177 LuPSMA 24-h SPECT/CT ( 177 Lu-SPECT) and early prostate-specific antigen (PSA) response., Design: Retrospective analysis of a clinical 177 Lu-PSMA-I&T treatment programme., Methods: In all, 125 men were treated with 6-weekly 177 LuPSMA-I&T [median 3 cycles, interquartile range (IQR): 2-4], median dose 8.0 GBq [95% confidence interval (CI): 7.5-8.0]. Imaging screening involved 68 GaPSMA-11 PET/diagnostic CT. 177 Lu-SPECT/diagnostic CT was acquired following each therapy, and clinical assessments 3-weekly. Following dose 2 (week 6), a composite PSA and 177 Lu-SPECT/CT imaging response [partial response (PR), stable disease (SD), and progressive disease (PD)] determined ongoing management. Response group (RG) 1 (marked reduction in PSA/imaging PR) break in treatment until subsequent PSA rise, then re-treatment. RG 2 (stable or reduced PSA and/or imaging SD) 6-weekly treatments until six doses, or no longer clinically benefitting. RG 3 (rise in PSA and/or imaging PD) recommended for an alternative treatment., Results: Overall PSA50% response rate (PSARR) was 60% (75/125), median PSA-PFS 6.1 months (95%CI: 5.5-6.7), and median OS 16.8 months (95%CI: 13.5-20.1). 35% (41/116) were classified as RG 1, 34% (39/116) RG 2, and 31% (36/116) RG 3. PSARRs by RG were 95% (38/41), 74% (29/39), and 8% (3/36); median PSA-PFS rates were 12.1 months (95%CI: 9.3-17.4), 6.1 months (95%CI: 5.8-9.0), and 2.6 months (95%CI: 1.6-3.1); and OS rates were 19.2 months (95%CI: 16.8-20.7), 13.2 months (95%CI: 12.0-18.8), and 11.2 months (95%CI: 8.7-15.6) for RG 1, 2, and 3, respectively. The median months of 'treatment holiday' for RG 1 was 6.1 months (IQR: 3.4-8.7). Nine men had received prior 177 LuPSMA-617 and were retreated with 177 LuPSMA-I&T, with a PSARR of 56% on re-treatment., Conclusion: Personalising dosing regimens using early response biomarkers with 177 LuPSMA has the potential to achieve similar treatment responses to continuous dosing while allowing treatment breaks or intensification. Further evaluation of early response biomarker-guided treatment regimens in prospective trials is warranted., Plain Language Summary: Lutetium-PSMA therapy is a new therapy for metastatic prostate cancer that is well tolerated and effective. However, not all men respond equally, with some responding very well and others progressing early. Personalising treatments require tools that can accurately measure treatment responses, preferably early in the treatment course, so adjustments to treatment can be made. Lutetium-PSMA can measure tumour sites after each therapy by taking whole body 3D images at 24 h using a small radiation wave from the treatment itself. This is called a SPECT scan. Previous work has shown that both prostate-specific antigen (PSA) response and changes in tumour volume on a SPECT scan can predict how patients will respond to treatment as early as dose 2. This study demonstrates that stratifying how men are treated based on the results of the 6-week SPECT scan and PSA response potentially allows a third of men to have break in treatment and that these men have both longer time to disease progression and OS. Men with an increase in tumour volume and increase in PSA early in treatment (6 weeks) had shorter time to disease progression and OS. Men with early biomarker disease progression were offered alternative treatments early in an attempt to allow the opportunity to allow a more effective potential therapy, if one was available. The study is an analysis of a clinical programme, and was not a prospective trial. As such, there are potential biases that could influence results. Hence, while the study is encouraging for the use of early response biomarkers to guide better treatment decisions, this must be validated in a well-designed clinical trial., Competing Interests: LE – Trials support – Novartis, Astellas, grant funding support from St Vincent’s Clinic Foundation. EH – Bayer Prostate Cancer Advisory Board (2022); Merck Urothelial Cancer Advisory Board (2021); Janssen Frailty in Oncology Advisory Board (2021); Ipsen Renal Cancer Advisory Board (2020, 2022) AG – Advisory Boards BMS, Merck, MSD, Regeneron, Sun Pharma; Unrestricted research support from Astra Zeneca and Sun Pharma No other authors have declared any conflicts of interest., (© The Author(s), 2023.)

177 Lu-PSMA is an effective treatment in metastatic castration-resistant prostate cancer (mCRPC). Our ability to assess response rates and adjust treatment may be improved using predictive tools. This study aimed to evaluate change in 177 Lu-PSMA SPECT quantitative parameters to monitor treatment response. Methods: One hundred twenty-seven men with progressive mCRPC previously treated with androgen-signaling inhibition (99%) and chemotherapy (71%) received a median of 3 (interquartile range [IQR], 2-5) 8-GBq (IQR, 8-8.5 GBq) doses of 177 Lu-PSMA-I&T. Imaging included 68 Ga-PSMA-11 PET/CT (SUV max > 15 at a single site and > 10 at all sites > 2 cm), diagnostic CT, and 177 Lu SPECT/CT from vertex to mid thigh (24 h after treatment). 177 Lu SPECT/CT quantitative analysis was undertaken at cycles 1 (baseline) and 2 (week 6) of treatment. Clinical and biochemical results were assessed to evaluate prostate-specific antigen (PSA) progression-free survival (PFS) and overall survival (OS). Results: A PSA reduction of more than 50% was seen in 58% (74/127). The median PSA PFS was 6.1 mo (95% CI, 5.5-6.7), and OS was 16.8 mo (95% CI, 13.5-20.1). At the time of analysis, 41% (52/127) were deceased. At baseline and week 6, 76% (96/127) had analyzable serial 177 Lu SPECT/CT imaging. SPECT total tumor volume (TTV) was reduced between baseline and week 6 in 74% (71/96; median, -193; IQR, -486 to -41). Any increase in SPECT TTV between baseline and week 6 was associated with significantly shorter PSA PFS (hazard ratio, 2.5; 95% CI, 1.5-4.2; P = 0.0008) but not OS. Median PSA PFS in those with an increase in SPECT TTV was 3.7 mo (95% CI, 2.8-6.8), compared with 6.7 mo (95% CI, 5.8-10.6) in those with no increase in SPECT TTV. An increase in SPECT TTV greater than 20% was also associated with PSA PFS (hazard ratio, 1.9; 95% CI, 1.2-3.0; P = 0.008) but less significantly than any change in SPECT TTV. There was a significant difference in PSA PFS between patients with both increased PSA and SPECT TTV and patients with reduced SPECT TTV and PSA (median, 2.8 vs. 9.0 mo; P < 0.0001). Conclusion: Increasing PSMA SPECT TTV on quantitative 177 Lu SPECT/CT predicts short progression-free survival and may play a future role as an imaging response biomarker, identifying when to cease or intensify 177 Lu-PSMA therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

177 Lu-PSMA-617 therapy has shown high prostate-specific antigen (PSA) response rates in men with metastatic castration-resistant prostate cancer. However, early treatment resistance is common. This LuPIN substudy aimed to determine the prognostic value of posttreatment quantitative PET for PSA progression-free survival (PFS) and overall survival (OS) with 177 Lu-PSMA-617 therapy. Methods: Fifty-six men with progressive metastatic castration-resistant prostate cancer were enrolled in the LuPIN trial and received up to 6 doses of 177 Lu-PSMA-617 and a radiation sensitizer (NOX66). 68 Ga-PSMA-11 and 18 F-FDG PET/CT, diagnostic CT, and bone scanning were performed at study entry and exit. Quantitative analysis tracked change in total tumor volume (TTV) and SUV. Univariable and multivariable analyses were conducted to examine the association of change in TTV (continuous and >30%), SUV max , PSA, and radiographic progression with PSA PFS and OS. Results: All men (37/56) who underwent both screening and posttreatment molecular imaging were analyzed; 70% (26/37) had a PSA response of more than 50%. Median PSA PFS was 8.6 mo, and median OS was 22 mo. Clinical progression had occurred at trial exit in 54% (20/37). In response to treatment, a reduced PSMA SUV max was demonstrated in 95% (35/37) and a reduced PSMA TTV in 68% (25/37). An increase in PSMA TTV by at least 30% was associated with worse OS (median, 10.2 vs. 23.6 mo; P = 0.002). Change in PSMA SUV max was not associated with PSA PFS or OS. 18 F-FDG SUV max was reduced in 51% (18/35) and 18 F-FDG TTV in 67% (22/35). An increased 18 F-FDG SUV max was associated with worse OS (median, 20.7 vs. 25.7 mo; P < 0.01). An 18 F-FDG TTV increase by more than 30% was associated with a short PSA PFS (median, 3.5 vs. 8.6 mo; P < 0.001) but not OS. Both PSA and radiographic progression were associated with shorter OS (median, 14.5 vs. 25.7 mo [ P < 0.001] and 12.2 vs. 23.6 mo [ P = 0.002]). On multivariable analysis, only increased PSMA TTV and PSA progression remained independently prognostic of OS (hazard ratio, 5.1 [95% CI, 1.5-17.1; P = 0.008] and 3.5 [95% CI, 1.1-10.9; P = 0.03], respectively). Conclusion: Change in quantitative PSMA TTV has strong potential as a prognostic biomarker with 177 Lu-PSMA-617 therapy, independent of 18 F-FDG PET parameters, PSA, or radiographic progression. Further research into the value of posttreatment PET as an imaging biomarker is warranted., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.

Background: Previously, results from the TheraP trial showed that treatment with lutetium-177 [ 177 Lu]Lu-PSMA-617 improved frequency of prostate-specific antigen (PSA) response rate and progression-free survival compared with cabazitaxel in men with metastatic castration-resistant prostate cancer. In this study, we aimed to analyse gallium-68 [ 68 Ga]Ga-PSMA-11 PET (PSMA-PET) and 2-[ 18 F]fluoro-2-deoxy-D-glucose PET (FDG-PET) imaging parameters as predictive and prognostic biomarkers in this patient population., Methods: TheraP was a multicentre, open-label, randomised phase 2 trial that recruited men with metastatic castration-resistant prostate cancer after treatment with docetaxel who were suitable for cabazitaxel from 11 hospitals in Australia. Participants were required to be 18 years old or older; have adequate haematological, renal, and liver function; and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned (1:1) using a centralised system using minimisation with a random component and that stratified patients by disease burden, previous treatment with enzalutamide or abiraterone, and study site. Patients were either given cabazitaxel (20 mg/m 2 intravenously every 3 weeks for up to ten cycles) or [ 177 Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles). The primary study endpoint, analysed previously, was PSA response rate. The prespecified tertiary study endpoint was association between total tumour quantitative parameters on PSMA-PET, FDG-PET, and baseline characteristics with clinical outcomes. A SUVmean of 10 or higher on PSMA-PET was evaluated as a predictive biomarker for response to [ 177 Lu]Lu-PSMA-617 versus cabazitaxel. A metabolic tumour volume (MTV) of 200 mL or higher on FDG-PET was tested as a prognostic biomarker. Both cutoff points were prespecified. The analysis was intention-to-treat, using logistic regression. This trial is registered with ClinicalTrials.gov, NCT03392428., Findings: 200 patients were randomly assigned between Feb 6, 2018, and Sept 3, 2019. 101 men were assigned to the cabazitaxel group and 99 were assigned to the [ 177 Lu]Lu-PSMA-617 group. The median follow-up at data cutoff of July 20, 2020, was 18·4 months (IQR 12·8-21·8). 35 (35%) of 99 men who were assigned [ 177 Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel had high PSMA uptake (SUVmean of ≥10). Odds of PSA response to [ 177 Lu]Lu-PSMA-617 versus cabazitaxel were significantly higher for men with SUVmean of 10 or higher compared with those with SUVmean of less than 10 (odds ratio [OR] 12·19 [95% CI 3·42-58·76] vs 2·22 [1·11-4·51]; p adj =0·039 for treatment-by-SUVmean interaction). PSA response rate for [ 177 Lu]Lu-PSMA-617 compared with cabazitaxel was 32 (91% [95% CI 76-98]) of 35 men versus 14 (47% [29-65]) of 30 men in patients with SUVmean of 10 or higher, and 33 (52% [39-64]) of 64 men versus 23 (32% [22-45]) of 71 men in those with SUVmean of less than 10. High-volume disease on FDG-PET (MTV ≥200 mL) was seen in 30 (30%) of 99 men who were assigned [ 177 Lu]Lu-PSMA-617 and 30 (30%) of 101 men who were assigned cabazitaxel. PSA response rate for both treatment groups combined for FDG-PET MTV of 200 mL or higher versus FDG-PET MTV of less than 200 mL was 23 (38% [95% CI 26-52]) of 60 men versus 79 (56% [48-65]) of 140 men (OR 0·44, 95% CI 0·23-0·84; p adj =0·035)., Interpretation: In men with metastatic castration-resistant prostate cancer, PSMA-PET SUVmean was predictive of higher likelihood of favourable response to [ 177 Lu]Lu-PSMA-617 than cabazitaxel, which provides guidance for optimal [ 177 Lu]Lu-PSMA-617 use. High FDG-PET MTV was associated with lower responses regardless of randomly assigned treatment, warranting further research for treatment intensification. A strength of this analysis is the validation of pre-specified cutpoints within a multicentre, randomised, controlled trial. Quantitative PET parameters used, however, require specialised software and are not yet routinely available in most clinics., Funding: Prostate Cancer Foundation of Australia, Endocyte (a Novartis Company), Australian Nuclear Science and Technology Organisation, Movember Foundation, It's a Bloke Thing, CAN4CANCER, The Distinguished Gentleman's Ride., Competing Interests: Declarations of interests MSH reports grants from Novartis, ANSTO, Bayer, Isotopia; and consulting fees for lectures or advisory boards from Astellas, AstraZeneca, Janssen, Merck Sharp and Dohme (MSD), Mundipharma, and Point Biopharma. LE reports personal fees from AstraZeneca, Janssen, Astellas, outside the submitted work. SS reports grants from Novartis, AstraZeneca, MSD, Genentech, Pfizer; and personal fees from AstraZeneca, MSD, Bristol Myer Squibb, and Novartis, outside the submitted work. AYZ reports personal fees from AstraZeneca, Bayer, Astellas, MSD, Novartis, Pfizer, Merck, and Bristol-Myers Squibb, outside the submitted work. AMS reports trial and research funding from AbbVie, EMD Serono, ITM, AVID, Medimmune, Telix, Adalta, Cyclotek, Theramyc; and personal fees from Life Science Pharmaceuticals, and Imagion, all outside the submitted work. AAA reports grants or personal fees from Janssen, Astellas, Novartis, Merck Serono, Tolmar, Amgen, Pfizer, Bayer, Telix Pharmaceuticals, Bristol-Myers Squibb, Sanofi, Noxopharm, AstraZeneca, Ipsen, MSD; and grants from GlaxoSmithKline, Aptevo Therapeutics, MedImmune, Bionomics, SYNthorx, Aculeus Therapeutics, Gilead, Eli Lilly, and Exelixis, all outside the submitted work. MRS reports grants from Astellas, Amgen, AstraZeneca, Bayer, Bionomics, Bristol-Myers Squibb, Celgene, Medivation, MSD, Pfizer, Roche, Sanofi, and Tilray; all outside the submitted work. IDD reports grants from National Health and Medical Research Council, during the conduct of the study; and institutional payments to support prostate cancer trials from Pfizer, ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, and MSD, outside the submitted work. IDD also reports being an unremunerated chair of ANZUP Cancer Trials Group. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: A diagnosis of cancer is associated with significant physical, psychological and financial burden. Including costs of cancer is an important component of shared decision making. Doctors bear a responsibility towards educating patients about the financial aspects of care. Multiple organisations have advocated for price transparency and implementing Informed Financial Consent in the clinic. However, few studies have evaluated the perspectives of oncologists on the current state of this discussion., Aims: The aim of this study is to determine the views and perspectives of medical oncologists regarding communication of costs and financial burden in patients with cancer., Methods: We conducted a prospective cross-sectional online survey via REDCap. The survey was distributed to medical oncologists and advanced trainees currently registered with Medical Oncology Group of Australia (MOGA). Data was collected using the online survey comprising socio-demographic characteristics, discussion of costs and financial burden, and facilitators and barriers to these discussions., Results: 547 members of MOGA were invited to participate in the study, and 106 of 547 MOGA members (19%) completed the survey. Most oncologists (66%) felt that it was their responsibility to discuss costs of care, however a majority of oncologists (59.3%) reported discussing costs with less than half of their patients. Only 25% of oncologists discussed financial concerns with more than half of their patients, and most oncologists were unfamiliar with cancer-related financial burden. Most Oncologists with greater clinical experience and those working in private practice were more likely to discuss costs with a majority of their patients., Conclusions: Certain characteristics of medical oncologists and their practices were associated with reported prevalence of discussing costs of care and financial burden with their patients. In the context of rising costs of cancer care, interventions targeting modifiable factors such as raising oncologist awareness of costs of care and financial burden, screening for financial toxicity and availability of costs information in an easily accessible manner, may help increase the frequency of patient-doctor discussions about costs of care, contributing to informed decision-making and higher-quality cancer care., Competing Interests: The authors have declared that no competing interests exist.

Aim: To evaluate a web-based tool for estimating and explaining three scenarios for expected survival time to people with advanced cancer (patients), their family members (FMs), and other healthcare professionals (HCPs)., Methods: Thirty-three oncologists estimated the "median survival of a group of similar patients" for patients seeking quantitative prognostic information. The web-based tool generated worst-case, most likely, and best-case scenarios for survival based on the oncologist's estimate. Oncologists presented the scenarios to each patient and provided a printed summary to patients, FMs, and HCPs. Attitudes to the information were assessed by questionnaires. Observed survival for each patient was compared with the oncologist's estimated survival and the three scenarios., Results: Prognosis was discussed with 222 patients: median age 67 years; 61% male; most common primary sites pancreas 15%, non-small-cell lung 15%, and colorectal 12%. The median (range) for observed survival times was 9 months (0.5-43) and for oncologist's estimated survival times was 12 months (2-96). Ninety-one percent of patients, 91% of FMs, and 84% of HCPs agreed that it was helpful having life expectancy explained as three scenarios. The majority (77%) of patients judged the information presented about their life expectancy to be the same or better than they had expected before the consultation. The survival estimates met a priori criteria for calibration, precision, and accuracy., Conclusions: Patients, FMs, and HCPs found it helpful to receive personalized prognostic information formatted as three scenarios for survival. It was feasible, acceptable, and safe to use a web-based resource to do this., (© 2022. The Author(s).)

Objective: The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with ≥3 lines of chemotherapy (PPS-ROC ≥3)., Methods: Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated ≥4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of ≤3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores ≥10 points above baseline in the QLQ-C30 summary score scale (range 0-100)., Results: Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC ≥3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC ≥3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC ≥3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline., Conclusion: Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants., Competing Interests: Competing interests: YCL has received honoraria from GSK for participation on the Advisory Board. FJ acknowledges institutional research grants from GSK and has received honoraria for educational events from AstraZeneca, Astellas, Amgen, BMS, Bayer, Clovis, GSK, Ipsen, MSD, Janssen, Pfizer, and Sanofi. AO acknowledges institutional research grants from MSD K.K., Fuji Pharma, Kissei Pharmaceutical, Meiji Holdings, Taiho Pharmaceutical, Kaken Pharmaceutical, Chugai Pharmaceutical, Tsumura, Daiichi Sankyo, Shinnihonseiyaku, Mochida Pharmaceutical, CMIC Holdings, CMIC Holdings, ASKA Pharmaceutical, Takeda, Pfizer, AstraZeneca, and Terumo; and has received honoraria for educational events from Takeda and AstraZeneca. JL acknowledges institutional research grants from AstraZeneca and MSD/Merck and has received honoraria for educational events from AstraZeneca, Neopharm, GSK and Pfizer and participated on the data safety monitoring board of Regeneron. JS has received honoraria (educational events/travel) from AstraZeneca, Clovis, Clovis and Roche; and has participated on the data safety monitoring board or advisory board for AstraZeneca, Clovis, Eisei, GSK, Novocure, Pfizer, Roche, and Tesaro. MLF acknowledges institutional research grants from AstraZeneca, Novartis, and Beigene; has received honoraria (consultancy/educational events) from AstraZeneca, Novartis, GSK, MSD, Takeda, Lily, and ACT-Genomics; and participated on the data safety monitoring board for AGITG. MTK, RO, AL, FH, AD, FTR, JB, PD, AMO, EA-L, JSB, DB, AF, M-CK, KD and MRS declare no conflict of interest., (© IGCS and ESGO 2022. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Purpose: The 2003 Leibovich score guides prognostication and selection to adjuvant clinical trials for patients with locally advanced renal cell carcinoma (RCC) after nephrectomy. We provide a robust external validation of the 2003 Leibovich score using contemporary data from SORCE, an international, randomized trial of sorafenib after excision of primary RCC., Methods: Data used to derive the 2003 Leibovich score were compared with contemporary data from SORCE. Discrimination and calibration of the metastasis-free survival outcome were assessed in data from patients with clear-cell RCC, using Cox proportional hazards regression, Kaplan-Meier curves, and calculation of Harrell's c indexes. Secondary analyses involved three important SORCE groups: patients with any non-clear-cell subtype, papillary, and chromophobe carcinomas., Results: Four hundred seven recurrences occurred in 982 patients in the Leibovich cohort and 520 recurrences were recorded in 1,445 patients in the primary SORCE cohort. Clear discrimination between intermediate-risk and high-risk SORCE cohorts was shown; hazard ratio 2.74 (95% CI, 2.29 to 3.28), c-index 0.63 (95% CI, 0.61 to 0.65). A hazard ratio of 0.61 (95% CI, 0.53 to 0.70) confirmed poor calibration of the two cohorts. Discrimination was observed in secondary populations, with c-indexes of 0.64 (95% CI, 0.59 to 0.69) for non-clear-cell RCC, 0.63 (95% CI, 0.56 to 0.69) for papillary RCC, and 0.65 (95% CI, 0.55 to 0.76) for chromophobe RCC., Conclusion: The 2003 Leibovich score discriminates between intermediate-risk and high-risk clear-cell and non-clear-cell RCC groups in contemporary data, supporting its use for risk stratification in adjuvant clinical trials. Over time, metastasis-free survival for patients with locally advanced RCC has improved. Contemporary data from adjuvant RCC trials should be used to improve prognostication for patients with RCC., Competing Interests: Tim EisenEmployment: AstraZeneca, RocheLeadership: AstraZeneca, RocheStock and Other Ownership Interests: AstraZeneca, RocheResearch Funding: Bayer (Inst), Pfizer (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AstraZeneca, RocheOther Relationship: Macmillan Cancer Support, Kidney Cancer UK Grant D. StewartHonoraria: Pfizer, Merck, EUSA PharmaConsulting or Advisory Role: Pfizer, Merck, EUSA Pharma, CMR SurgicalSpeakers' Bureau: PfizerResearch Funding: Pfizer, AstraZeneca, Intuitive Surgical, CRUKTravel, Accommodations, Expenses: Pfizer Axel BexConsulting or Advisory Role: Pfizer (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst), Eisai (Inst), Genentech (Inst)Speakers' Bureau: Pfizer, Novartis, Bristol Myers SquibbResearch Funding: Pfizer (Inst) Rick KaplanResearch Funding: AstraZeneca (Inst) Ian D. DavisResearch Funding: Astellas Pharma (Inst), Pfizer (Inst), Roche/Genentech (Inst), MSD Oncology (Inst), AstraZeneca (Inst), Janssen Oncology (Inst), Eisai (Inst), Bayer (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Movember Foundation (Inst), Exelixis (Inst), Ipsen (Inst), Medivation (Inst), Seattle Genetics (Inst), ANZUP Cancer Trials GroupPatents, Royalties, Other Intellectual Property: International Patent Application No: PCT/US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research Martin R. StocklerResearch Funding: Astellas Pharma (Inst), Celgene (Inst), Bayer (Inst), Bionomics (Inst), Medivation (Inst), Sanofi (Inst), Pfizer (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Amgen (Inst), Merck Sharp & Dohme (Inst), Tilray (Inst), BeiGene (Inst)Travel, Accommodations, Expenses: Medivation/Pfizer Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Amgen (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Exelixis (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Peloton Therapeutics (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Bernard EscudierHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, OncorenaConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Ipsen, AVEO, OncorenaResearch Funding: BMS France (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Ipsen, MSD James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Steven JoniauConsulting or Advisory Role: Janssen, AstraZeneca, Bayer, Astellas PharmaSpeakers' Bureau: Astellas Pharma, Janssen, IpsenResearch Funding: Janssen (Inst), Astellas Pharma (Inst), Ipsen (Inst), Bayer (Inst), Ferring (Inst)Travel, Accommodations, Expenses: Janssen, Ipsen, Astellas Pharma, Ferring Joaquim BellmuntStock and Other Ownership Interests: Rainier TherapeuticsHonoraria: UpToDateConsulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers SquibbResearch Funding: Millennium (Inst), Sanofi (Inst), Pfizer/EMD Serono (Inst)Travel, Accommodations, Expenses: Pfizer, MSD Oncology, Ipsen Mahesh K.B. ParmarResearch Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Janssen (Inst), Clovis Oncology (Inst) Angela MeadeResearch Funding: AstraZeneca (Inst)No other potential conflicts of interest were reported. Tim EisenEmployment: AstraZeneca, RocheLeadership: AstraZeneca, RocheStock and Other Ownership Interests: AstraZeneca, RocheResearch Funding: Bayer (Inst), Pfizer (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AstraZeneca, RocheOther Relationship: Macmillan Cancer Support, Kidney Cancer UK Grant D. StewartHonoraria: Pfizer, Merck, EUSA PharmaConsulting or Advisory Role: Pfizer, Merck, EUSA Pharma, CMR SurgicalSpeakers' Bureau: PfizerResearch Funding: Pfizer, AstraZeneca, Intuitive Surgical, CRUKTravel, Accommodations, Expenses: Pfizer Axel BexConsulting or Advisory Role: Pfizer (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst), Eisai (Inst), Genentech (Inst)Speakers' Bureau: Pfizer, Novartis, Bristol Myers SquibbResearch Funding: Pfizer (Inst) Rick KaplanResearch Funding: AstraZeneca (Inst) Ian D. DavisResearch Funding: Astellas Pharma (Inst), Pfizer (Inst), Roche/Genentech (Inst), MSD Oncology (Inst), AstraZeneca (Inst), Janssen Oncology (Inst), Eisai (Inst), Bayer (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Movember Foundation (Inst), Exelixis (Inst), Ipsen (Inst), Medivation (Inst), Seattle Genetics (Inst), ANZUP Cancer Trials GroupPatents, Royalties, Other Intellectual Property: International Patent Application No: PCT/US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research Martin R. StocklerResearch Funding: Astellas Pharma (Inst), Celgene (Inst), Bayer (Inst), Bionomics (Inst), Medivation (Inst), Sanofi (Inst), Pfizer (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Amgen (Inst), Merck Sharp & Dohme (Inst), Tilray (Inst), BeiGene (Inst)Travel, Accommodations, Expenses: Medivation/Pfizer Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Amgen (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Exelixis (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Peloton Therapeutics (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Bernard EscudierHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, OncorenaConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Ipsen, AVEO, OncorenaResearch Funding: BMS France (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Ipsen, MSD James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Steven JoniauConsulting or Advisory Role: Janssen, AstraZeneca, Bayer, Astellas PharmaSpeakers' Bureau: Astellas Pharma, Janssen, IpsenResearch Funding: Janssen (Inst), Astellas Pharma (Inst), Ipsen (Inst), Bayer (Inst), Ferring (Inst)Travel, Accommodations, Expenses: Janssen, Ipsen, Astellas Pharma, Ferring Joaquim BellmuntStock and Other Ownership Interests: Rainier TherapeuticsHonoraria: UpToDateConsulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers SquibbResearch Funding: Millennium (Inst), Sanofi (Inst), Pfizer/EMD Serono (Inst)Travel, Accommodations, Expenses: Pfizer, MSD Oncology, Ipsen Mahesh K.B. ParmarResearch Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Janssen (Inst), Clovis Oncology (Inst) Angela MeadeResearch Funding: AstraZeneca (Inst)No other potential conflicts of interest were reported.

Objective: To determine whether the addition of inhaled methoxyflurane to periprostatic infiltration of local anaesthetic (PILA) during transrectal ultrasonography-guided prostate biopsies (TRUSBs) improved pain and other aspects of the experience., Patients and Methods: We conducted a multicentre, placebo-controlled, double-blind, randomized phase 3 trial, involving 420 men undergoing their first TRUSB. The intervention was PILA plus a patient-controlled device containing either 3 mL methoxyflurane, or 3 mL 0.9% saline plus one drop of methoxyflurane to preserve blinding. The primary outcome was the pain score (0-10) reported by the participant after 15 min. Secondary outcomes included ratings of other aspects of the biopsy experience, willingness to undergo future biopsies, urologists' ratings, biopsy completion, and adverse events., Results: The mean (SE) pain scores 15 min after TRUSB were 2.51 (0.22) in those assigned methoxyflurane vs 2.82 (0.22) for placebo (difference 0.31, 95% confidence interval [CI] -0.75 to 0.14; P = 0.18). Methoxyflurane was associated with better scores for discomfort (difference -0.48, 95% CI -0.92 to -0.03; P = 0.035, adjusted [adj.] P = 0.076), whole experience (difference -0.50, 95% CI -0.92 to -0.08; P = 0.021, adj. P = 0.053), and willingness to undergo repeat biopsies (odds ratio 1.67, 95% CI 1.12-2.49; P = 0.01) than placebo. Methoxyflurane resulted in higher scores for drowsiness (difference +1.64, 95% CI 1.21-2.07; P < 0.001, adj. P < 0.001) and dizziness (difference +1.78, 95% CI 1.31-2.24; P < 0.001, adj. P < 0.001) than placebo. There was no significant difference in the number of ≥ grade 3 adverse events., Conclusions: We found no evidence that methoxyflurane improved pain scores at 15 min, however, improvements were seen in patient-reported discomfort, overall experience, and willingness to undergo repeat biopsies., (© 2021 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Purpose: We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL)., Methods: HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible)., Results: HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9; P < .001), cognitive function (4.0, 95% CI, 2.5 to 5.5; P < .001), and physical function (2.6, 95% CI, 1.3 to 3.9; P < .001), but not OHQL (1.2, 95% CI, -0.2 to 2.7; P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17%; P < .0001), cognitive function (31% v 20%; P = .001), and physical function (31% v 22%; P < .001), but not fatigue (24% v 18%; P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics., Conclusion: Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL., Competing Interests: Martin R. StocklerSpeakers' Bureau: Astellas PharmaResearch Funding: Astellas, Celgene, Bayer, Bionomics, Medivation, Sanofi, Pfizer, AstraZeneca, Bristol Myers Squibb, Roche, Amgen, Merck Sharp & Dohme, Tilray, BeiGeneExpert Testimony: Medivation/Pfizer Ian D. DavisResearch Funding: Astellas Pharma, Pfizer, Roche/Genentech, MSD Oncology, AstraZeneca, Janssen Oncology, Eisai, Bayer, Amgen, Bristol Myers Squibb, Movember Foundation, Exelixis, Ipsen, Medivation, SeagenPatents, Royalties, Other Intellectual Property: International Patent Application No: PCT/US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research Haryana M. DhillonHonoraria: Janssen Oncology Stephen D. BegbieHonoraria: Janssen OncologyConsulting or Advisory Role: Astellas Pharma, MSD Oncology, Merck SeronoSpeakers' Bureau: Astellas MedivationResearch Funding: Merck Serono, Janssen Oncology, Boston Biomedical, Pfizer/EMD Serono, Bristol Myers Squibb Kim N. ChiStock and Other Ownership Interests: JanssenHonoraria: Astellas Pharma, Bayer, AstraZeneca, Roche, Merck, ESSAConsulting or Advisory Role: Astellas Pharma, Janssen, Sanofi, Amgen, Bayer, AstraZeneca, Roche, POINT Biopharma, Daiichi Sankyo, Merck, Constellation PharmaceuticalsSpeakers' Bureau: JanssenResearch Funding: Astellas Pharma, Bayer, Sanofi, Bristol Myers Squibb, Merck, Roche, AstraZeneca, Novartis, Pfizer, ESSAPatents, Royalties, Other Intellectual Property: AstraZenecaExpert Testimony: Novartis Simon ChowdhuryStock and Other Ownership Interests: Clovis OncologyHonoraria: Novartis, Clovis OncologyConsulting or Advisory Role: Astellas Pharma, Bayer, Pfizer, Janssen-Cilag, BeiGene, NovartisSpeakers' Bureau: Janssen-Cilag, Sanofi/Aventis Mark FrydenbergEmployment: Genesis Cancer Care, Telix Pharmaceuticals Lisa G. HorvathEmployment: Connected Medical SolutionsLeadership: Connected Medical SolutionsStock and Other Ownership Interests: Imagion BiosystemsHonoraria: Imagion BiosystemsSpeakers' Bureau: Astellas PharmaExpert Testimony: Astellas PharmaTravel, Accommodations, Expenses: Janssen-Cilag, Pfizer Anthony M. JoshuaStock and Other Ownership Interests: Pricilium TherapeuticsConsulting or Advisory Role: Neoleukin Therapeutics, Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Noxopharm, IQvia, Pfizer, Novartis, Bristol Myers Squibb, Merck Serono, EisaiResearch Funding: Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, Macrogenics, Lilly, Pfizer, AstraZeneca, Corvus Pharmaceuticals, Lilly Gavin M. MarxStock and Other Ownership Interests: JanssenHonoraria: RocheConsulting or Advisory Role: Janssen Ray McDermottStock and Other Ownership Interests: BayerHonoraria: Sanofi, Janssen, Astellas Pharma, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Novartis, Clovis OncologyConsulting or Advisory Role: MSD OncologyResearch Funding: Janssen, Bayer, Astellas PharmaExpert Testimony: PfizerTravel, Accommodations, Expenses: Janssen-Cilag, Roche, Ipsen Scott A. NorthStock and Other Ownership Interests: Janssen-OrthoHonoraria: Astellas Pharma, Pfizer, Sanofi, Merck, Roche Canada, BMSConsulting or Advisory Role: Sanofi, Pfizer, Roche Canada, Merck, AstraZeneca, Janssen, Bristol Myers Squibb, EMD SeronoSpeakers' Bureau: Astellas PharmaResearch Funding: Janssen, AstraZenecaExpert Testimony: AstraZenecaTravel, Accommodations, Expenses: Astellas Pharma Francis ParnisHonoraria: Janssen OncologyConsulting or Advisory Role: Ipsen, Merck Serono M. Neil ReaumeStock and Other Ownership Interests: NovartisHonoraria: Ipsen, AstraZeneca, Pfizer, EMD SeronoSpeakers' Bureau: AstraZeneca Shahneen SandhuStock and Other Ownership Interests: Bristol Myers SquibbHonoraria: Merck, Merck Serono, AstraZenecaConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb/Roche, Bristol Myers SquibbSpeakers' Bureau: Merck, Roche/Genentech, AmgenResearch Funding: AstraZeneca, Merck, Endocyte/Advanced Accelerator Applications, Genentech/Roche, Novartis Thean Hsiang TanSpeakers' Bureau: Janssen Oncology Alastair ThomsonConsulting or Advisory Role: Novartis, RocheSpeakers' Bureau: Genomic Health, Novartis, LillyTravel, Accommodations, Expenses: Ipsen, BMS, Astellas Pharma, EUSA Pharma Francisco Vera-BadilloHonoraria: BayerConsulting or Advisory Role: AstraZeneca, Janssen OncologySpeakers' Bureau: AstraZeneca/MedImmune Scott G. WilliamsHonoraria: AmgenConsulting or Advisory Role: JanssenExpert Testimony: Astellas Pharma Alison Y. ZhangStock and Other Ownership Interests: Astellas PharmaHonoraria: Mundipharma, AstraZeneca, Pfizer, Bayer, MSD Oncology, Merck Sharp & DohmeConsulting or Advisory Role: Janssen Oncology, Pfizer, Merck Robert R. ZielinskiStock and Other Ownership Interests: BMSHonoraria: Pfizer, Roche/GenentechConsulting or Advisory Role: MSD OncologySpeakers' Bureau: BMSiResearch Funding: AstraZeneca Christopher J. SweeneyStock and Other Ownership Interests: LeuchemixConsulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, LillyResearch Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, PfizerPatents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide; Exelixis: Abiraterone plus cabozantinib combinationNo other potential conflicts of interest were reported.

Background: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC., Methods: Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1)., Findings: Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5-3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4-36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity., Interpretation: Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors., Funding: None., Competing Interests: Declaration of Competing Interest E.M.K.: Honoraria – Janssen, Ipsen, Astellas Pharma, Research Review; Consulting or Advisory Role – Astellas Pharma, Janssen, Ipsen; Research Funding – Astellas Pharma, AstraZeneca; Travel & accommodation – Astellas Pharma, Pfizer, Ipsen, Roche.B.T.: Grants and personal fees – Amgen, AstraZeneca, Astellas, BMS, Janssen, Pfizer, MSD, Ipsen, Bayer; Personal fees – IQVIA, Sanofi, Tolmar, Novartis, Roche.A.Z.: Advisory Role – Astellas; Honoraria – Astellas; Grants and personal fees – Astra Zeneca, Pfizer; Personal fees – Merck Sharp & Dome, Bayer, Mundipharma, Janssen.I.D.D.: Institutional funding – Pfizer, ANZUP Cancer Trials Group, Bayer, Astellas, Janssen, Movember Foundation, Merck Sharp & Dome; Unremunerated chair of ANZUP Cancer Trials Group.T.S.: Travel – Astra Zeneca.D.R.S.: Grants – Regeneron, Amgen, Arrowhead, Espirion, Novartis; Personal fees – Amgen, Sanofi.A.A.: Consultant – Astellas, Janssen, Novartis; Speakers Bureau – Astellas, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb; Merck Serono, Bayer; Honoraria – Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dome; Scientific Advisory Board – Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono; Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dome, Amgen, Noxopharm; Travel & accommodation – Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer; Investigator research funding – Astellas, Merck Serono, Astra Zeneca; Institutional research funding – Bristol Myers Squibb, Astra Zeneca, Aptevo Therapeutics, Glaxo Smith Kline, Pfizer, MedImmune, Astellas, SYNthorx, Bionomics, Sanofi Aventis, Novartis, Ipsen.A.M.J.: Insitutional funding – Pfizer, Astellas.L.G.H.: Research funding – Astellas; Travel sponsorship – Janssen, Pfizer; Honoraria – Imagion Biosystems. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)