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Introduction: Combination of abiraterone with androgen deprivation therapy (ADT) has better survival outcomes than ADT alone in metastatic Hormone-sensitive prostate cancer (mHSPC) in the Western population. In this prospective (Clinical Trials Registry-India [CTRI] registered) observational study, we present the comparative oncological outcomes of ADT alone and ADT + abiraterone in Indian patients, which is not available currently. Methods: This study (CTRI-number-CTRI/2020/07/026545) included newly diagnosed mHSPC patients from January 2020 to June 2023 in a tertiary care hospital, urology department. Patients fulfilling inclusion criteria were advised ADT with abiraterone (A + ADT), and those not affording received ADT monotherapy (ADT). The primary endpoint was overall survival (OS). Secondary outcomes included prostate-specific antigen (PSA) decline >90%, radiographic progression-free survival (rPFS), and PSA progression-free survival (pPFS). Results: Out of278 patients with mHSPC, 163 patients were excluded and 115 were analyzed (ADT = 40 vs. A + ADT = 75). After a median follow-up of 20.3 months, 11 of 40 (27.5%) in ADT-only arm and 15 of 75 (20%) in ADT + abiraterone arm had died (Hazard-ratio of death 0.72; 95% confidence interval 0.68-0.88; P < 0.001). A PSA decline of >90% was seen in 85% in the ADT alone group and 93.3% in the ADT + abiraterone group. Significantly better outcomes of the ADT + abiraterone were seen in the secondary endpoints of rPFS (P < 0.001) and pPFS (P < 0.001). The OS benefit was 28% reduction in risk of death in our study versus 37% and 38% in STAMPEDE and LATITUDE, respectively. pPFS and rPFS were also poorer in Indian subsets. Conclusions: Abiraterone with ADT improves OS, PSA response, rPFS, and pPFS in the Indian population akin to the Western data but with poorer OS, rPFS, and PSA progression-free survival on comparison. [ABSTRACT FROM AUTHOR]

Women around the world are most frequently afflicted with breast cancer, and it is one of the most frequent causes of cancer death in females. Breast cancer is usually classified according to biomarker status, triple‐negative breast cancer (TNBC) represents a distinct subtype characterized by immunohistochemical findings that denote negativity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her-2) on cancer tissue. It is more common in younger women than in other subtypes. As an invasive breast cancer subtype with a unique drug-resistant phenotype and metastatic burden, it has limited treatment options, and patients have a poor prognosis with high rates of local, distant recurrence and mortality, and there is still a lack of standardized treatment protocols for TNBC. In this review, we delve into the current treatment strategies for TNBC and explore the potential for new approaches and targets in the future. This trial is registered with NCT03997123. [ABSTRACT FROM AUTHOR]

Simple Summary: Salivary duct carcinomas (SDC) can present with distinct immunologic profiles similar to breast cancer, such as androgen receptor (AR) and HER-2/Neu-positivity, raising the hypothesis that these tumors may respond to hormonal signaling. No consensus exists on how to best manage this entity. The data evaluating the use of targeted therapies, such as androgen deprivation therapy and HER-2 receptor inhibitors, in the front-line setting when treating curatively is limited. We studied patients with AR+ SDC, demonstrating high rates of control and survival using an aggressive approach to treatment. Immunoprofiles were highly variable, highlighting the potential for future treatment individualization. We hope that this may allow for personalization of treatment in the future, using molecular profiling to determine whether the addition of biological agents in the definitive setting against specific targets, such as AR and HER-2/Neu, will further improve outcomes for these patients. Background: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. Methods: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan–Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). Results: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8–6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. Conclusion: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients. [ABSTRACT FROM AUTHOR]

Copyright of Die Urologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P  < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS. Patients and Methods Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. Results In ARASENS, 54 Black patients received darolutamide (n  = 26) or placebo (n  = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs.12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%). Conclusion In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of biomarkers that can predict the effectiveness of treatments for metastatic castration-resistant prostate cancer (mCRPC) has been a recent challenge. We focused on the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker after enzalutamide administration. A retrospective subgroup analysis and prognostic survey were conducted on 43 patients with mCRPC and bone metastases. The results showed that patients with no detected CTCs at baseline showed significantly longer overall survival (OS) than those with CTCs at baseline. Furthermore, patients who exhibited a negative reversion of CTC status during enzalutamide treatment had significantly longer OS compared to patients with persistent CTC positivity. Achieving CTC-negative reversion during treatment for mCRPC with bone metastases was associated with improved long-term OS. Chronological measurement of CTC status might be clinically useful in the treatment of mCRPC. Enzalutamide is a second-generation androgen receptor inhibitor that increases overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker following enzalutamide administration. A retrospective subgroup analysis and prognostic survey were conducted on 43 patients with mCRPC and bone metastases treated in Juntendo University-affiliated hospitals from 2015 to 2022. Patients were treated with 160 mg enzalutamide daily. CTC analyses on blood samples were performed regularly before and every three months after treatment. The relationship between the patients' clinical factors and the OS rate was analyzed using the log-rank test; the median OS was 37 months. Patients with no detected CTCs at baseline showed significantly longer OS than those with detectable CTCs at baseline. Furthermore, patients demonstrating negative reversion of CTCs during enzalutamide treatment had significantly longer OS than patients with CTC-positivity. Two biomarkers—higher hemoglobin at baseline and achieving negative reversion of CTCs—were significantly associated with prolonged OS. This study suggests that patients achieving CTC-negative reversion during treatment for mCRPC with bone metastases exhibit improved long-term OS. Chronological measurement of CTC status might be clinically useful in the treatment of mCRPC. [ABSTRACT FROM AUTHOR]

Simple Summary: The efficacy of abiraterone plus prednisolone (ABI) against nonmetastatic castration-resistant prostate cancer (CRPC) remains unclear. To evaluate enzalutamide and ABI as the first-line treatment for CRPC, we conducted the randomized controlled trial including both metastatic and nonmetastatic CRPC. As a sub-analysis, we focused on nonmetastatic CRPC in this study. ABI and enzalutamide had similar efficacy and safety profiles in patients with nonmetastatic CRPC. Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) can improve the survival of patients with castration-resistant prostate cancer (CRPC). However, the agent that is more effective against nonmetastatic CRPC remains unclear. To evaluate the agent that can be used as the first-line treatment for CRPC, an investigator-initiated, multicenter, randomized controlled trial (ENABLE Study for PCa) including both metastatic and nonmetastatic CRPC was conducted in Japan. The prostate-specific antigen (PSA) response rate, overall survival, some essential survival endpoints, and safety of patients with nonmetastatic CRPC were also analyzed. In this subanalysis, 15 and 26 patients in the ENZ and ABI arms, respectively, presented with nonmetastatic CRPC. There was no significant difference in terms of the PSA response rate between the ENZ and ABI arms (80% and 64%, respectively; p = 0.3048). The overall survival did not significantly differ between the two arms (HR: 0.68; 95% CI: 0.22–2.14, p = 0.5260). No significant differences were observed in terms of radiographic progression-free survival and cancer-specific survival between the ENZ and ABI arms (HR: 0.81; 95% CI: 0.35–1.84; p = 0.6056 and HR: 0.72; 95% CI: 0.19–2.73; p = 0.6443, respectively). Only four and six patients in the ENZ and ABI arms, respectively, had ≥grade 3 adverse events. ABI and ENZ had similar efficacy and safety profiles in patients with nonmetastatic CRPC. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer (PCa) affects millions of men worldwide, and the mortality rate for locally advanced or metastasized cancer cases remains high. Despite the development of various therapies and approaches, their efficacies still need to be investigated further. This review summarizes the radiotherapy-centered therapeutic combinations and trials that have been tested for the treatment of localized PCa while providing insights into their efficacy and complications. Prostate cancer (PCa) used to be one of the most common nondermatologic cancers in men that can be treated only with surgery. However, a revolutionary breakthrough came in the 1980s with the introduction of long-acting luteinizing hormone-releasing hormone (LHRH) agonists for the curative treatment of PCa. This paradigm shift contributed to the combined use of androgen deprivation therapy (ADT), chemotherapy, and radiotherapy for the treatment. The latest data highlight the use of treatment intensification (TI), i.e., combined use of radiotherapy (RT) and hormonal or drug treatments, for localized or locally advanced PCa. Indeed, the results of combined modality treatments have shown a reduction in disease-specific mortality and improved overall survival. Although TI seems promising, more research studies are warranted to confirm its efficacy. This review summarizes the latest available outcome results of pivotal trials and clinical studies on the efficacy of TI. [ABSTRACT FROM AUTHOR]

Knowledge on survival probabilities is essential for determining optimal treatment strategies. We studied overall survival and associated prognostic factors in Dutch patients with localised prostate cancer (PCa) selected for external beam radiotherapy. For this single-centre retrospective cohort study, we identified all T1-T3 PCa patients (aged 55–80 years) in the radiotherapy planning database with a start date between January 2006 and December 2013, treated with 72–78 Gy in 2 Gy fractions to the prostate ± seminal vesicles (n = 1536). Long-term androgen deprivation therapy (ADT) was predominantly prescribed in the case of extracapsular disease (>T3). Overall survival was estimated using the Kaplan–Meier method. Prognostic factors were evaluated in Cox regression models for the intermediate-risk and high-risk groups. The median follow-up was 12 years for patients who were alive. Ten-year survival rates were 79.0% for low-risk (n = 120), 59.9% for intermediate-risk (n = 430) and 56.8% for high-risk patients (n = 986). A higher age, higher comorbidity score, active smoking and Gleason score ≥8 had a statistically significant negative impact on overall survival at multivariable analysis. ADT was associated with superior overall survival in the high-risk group translating into overall survival rates similar to the intermediate-risk group. Although PCa patients selected for external beam radiotherapy are typically in good health, their comorbidity score and smoking habits appeared to be dominant predictors for overall survival. Overall survival rates within the high-risk group varied, showing improved overall survival with ADT prescription and worse overall survival in the case of Gleason score ≥8. • Comorbidity score and smoking status are important predictors for overall survival. • Overall survival for T3 patients with adjuvant hormonal therapy was high. • Only the tumour characteristic Gleason score ≥8 was prognostic within risk groups. • 10-year survival rates within high-risk subgroups varied between 30 and 80%. [ABSTRACT FROM AUTHOR]

For metastatic hormone naïve prostate cancer patients, androgen deprivation therapy (ADT) with escalation therapy including docetaxel and/or androgen targeting drugs is the standard therapy. However, de-escalation is preferable to avoid unnecessary side effects, especially from docetaxel, but markers to identify these patients are lacking. The purpose of the present study was to investigate the potential of PSA and Ki67 immunoreactive scores as prognostic and treatment-predictive markers. Prostate biopsies from 92 patients with metastatic hormone naïve PC (PSA > 80 ng/mL or clinical metastases) were immunohistochemically evaluated for PSA and Ki67. Gene expression analysis was performed with Clariom D microarrays to identify the phenotypic profile associated with the immunohistochemistry scores of biopsies. Cox regression analysis for progression free survival after ADT adjustment for age, ISUP, and serum PSA and Kaplan-Meier analyses were performed to assess prognostic values of Ki67, PSA, and the Ki67/PSA ratio. The immunohistochemical score for PSA was the strongest prognostic factor for progression-free and overall survival after ADT. Consequently, the ratio between Ki67 and PSA displayed a stronger prognostic value than Ki67 itself. Further, mRNA expression data analysis showed an association between high Ki67/PSA ratio, cell-cycle regulation, and DNA damage repair. In an exploratory sub-analysis of 12 patients treated with early docetaxel as addition to ADT and matched controls, a high Ki67/PSA ratio showed potential to identify those who benefit from docetaxel. PSA and Ki67 immunoreactive scores are prognostic in the metastatic hormone-sensitive setting, with PSA being superior. The combination of Ki67 and PSA did not give additional prognostic value. The results suggest immunohistochemical scoring of PSA to have potential to improve identification of patients responding well to ADT alone. [ABSTRACT FROM AUTHOR]

Copyright of Die Urologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The management of metastatic prostate cancer continues to evolve. Recent developments include a significant change in the standard of care for first-line treatment in those with hormone sensitive disease and newly approved combinations in castrate resistant disease. Additionally, a radioligand has been approved for selected patients with castrate resistant disease. [ABSTRACT FROM AUTHOR]

Simple Summary: In this exploratory analysis of a randomized controlled trial, we found that dynamic changes in simple laboratory-based markers such as prostate-specific antigen (PSA) could be used to predict survival in patients with metastatic prostate cancer that is sensitive to hormonal manipulation. We developed a model that captures information on dynamic changes in PSA along with hemoglobin (Hb), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR), and this model was found to be clinically more useful compared to the "treat all" strategy. This model could be used to design future adaptive trials that will investigate sequential treatment personalization in metastatic hormone sensitive prostate cancer patients. We investigated whether inter-patient variation in the dynamic trajectory of hemoglobin (Hb), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and prostate-specific antigen (PSA) can prognosticate overall survival (OS) in de novo mHSPC. This is a secondary analysis of the LATITUDE trial in which high-risk de novo mHSPC patients were randomly assigned to receive either androgen deprivation therapy (ADT) plus abiraterone or ADT plus placebo. We used a five-fold cross-validated joint model approach to determine the association of temporal changes in the serological markers with OS. Decision curve analysis was applied to determine the net benefit. When dynamic changes in Hb, LMR, NLR, PLR, and PSA were included in a multivariate joint model, an increase in the log of the current value of PSA (HR: 1.24 [1.20–1.28]) was associated with inferior OS. A multivariate joint model that captured dynamic trajectory of Hb, NLR, PLR, LMR, and PSA up to 24 months, showed a net benefit over the "treat all" strategy at a threshold of probability of approximately ≥30% while no net benefit was seen when dynamic change in PSA was omitted. Our joint model could be used for designing future adaptive trials investigating sequential treatment personalization. [ABSTRACT FROM AUTHOR]

Visceral metastasis (VM) and a higher number of bone metastasis generally define high volume/risk in patients with metastatic castration-sensitive prostate cancer (mCSPC). Subgroup analysis of pivotal trials did not show a clear benefit of second-generation non-steroidal anti-androgens (NSAAs) in patients with VM. However, subgroup analysis of the trial assessing abiraterone acetate, a CYP 17 inhibitor, plus prednisone (AAP) showed an improved overall survival (OS) in patients with mCSPC with VM. We searched MEDLINE, Web of Science, and congress abstracts for the phase III randomized controlled trials of second-generation NSAAs and AAP in patients with mCSPC. In this pooled analysis, we included 6485 patients from the 6 phase III trials. The rate of patients with VM was 15.2%. Interestingly, in contrast to NSAAs, AAP seems to be effective in improving OS among patients with VM (hazard ratio, HR: 0.89, 95% CI, 0.72-1.11, P =.30 for second-generation NSAAs; HR: 0.58, 95% CI, 0.40-0.84, P =.004 for AAP). In contrast, both second-generation NSAAs (HR: 0.63, 95% CI, 0.57-0.70, P <.001) and AAP (HR: 0.68, 95% CI, 0.57-0.81, P <. 001) improved OS in patients without VM. In this pooled analysis, we demonstrate that while AAP provided an OS improvement in patients with VM, second-generation NSAAs did not demonstrate a similar OS benefit in this population. [ABSTRACT FROM AUTHOR]

Simple Summary: This is the first study that has investigate the potential role of the SRRT gene in prostate cancer using clinical samples. We found that high expression of SRRT was significantly associated with poor overall and cause-specific survival. High SRRT expression was also significantly associated with high Gleason score, PSA abundance, pathological T category, and common genomic aberrations in PCa such as PTEN loss, ERG gain, mutant TP53, or ATM. Gene set enrichment analysis suggested that SRRT may play a role in regulating the expression of genes contributing to prostate cancer aggressiveness. Our findings suggest that SRRT could be a prognostic and diagnostic biomarker for lethal PCa, as well as a potential therapeutic target. Arsenite-resistance protein 2, also known as serrate RNA effector molecule (ARS2/SRRT), is known to be involved in cellular proliferation and tumorigenicity. However, its role in prostate cancer (PCa) has not yet been established. We investigated the potential role of SRRT in 496 prostate samples including benign, incidental, advanced, and castrate-resistant patients treated by androgen deprivation therapy (ADT). We also explored the association of SRRT with common genetic aberrations in lethal PCa using immunohistochemistry (IHC) and performed a detailed analysis of SRRT expression using The Cancer Genome Atlas (TCGA PRAD) by utilizing RNA-seq, clinical information (pathological T category and pathological Gleason score). Our findings indicated that high SRRT expression was significantly associated with poor overall survival (OS) and cause-specific survival (CSS). SRRT expression was also significantly associated with common genomic aberrations in lethal PCa such as PTEN loss, ERG gain, mutant TP53, or ATM. Furthermore, TCGA PRAD data revealed that high SRRT mRNA expression was significantly associated with higher Gleason scores, PSA levels, and T pathological categories. Gene set enrichment analysis (GSEA) of RNAseq data from the TCGA PRAD cohort indicated that SRRT may play a potential role in regulating the expression of genes involved in prostate cancer aggressiveness. Conclusion: The current data identify the SRRT's potential role as a prognostic for lethal PCa, and further research is required to investigate its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Simple Summary: This propensity-score-matched study showed significantly higher incidence and effects of osteoporotic fracture in patients with localized or regional SEER-staged prostate cancer treated with androgen deprivation therapy. This study evaluated the effect of androgen deprivation therapy (ADT) on osteoporotic fractures (OF) and its prognostic effect on overall survival in patients with localized or regional prostate cancer (PC) using the Korean National Insurance Dataset. A total of 8883 pairs of 1:1 propensity-score-matched patients with localized or regional PC were retrospectively enrolled between 2007 and 2016. All patients underwent at least 1 year of follow-up to evaluate therapeutic outcomes. Multivariate analysis was performed to determine the prognostic effect of ADT on OF. During a mean follow-up of 47.7 months, 977 (3.43%) patients developed OF, and the incidences of hip, spine, and wrist fractures were significantly different between ADT and non-ADT groups (p < 0.05). The ADT group had a significantly higher incidence of OF (hazard ratio 2.055, 95% confidence interval 1.747–2.417) than the non-ADT group (p < 0.05), and the incidence of spine/hip/wrist OF was significantly higher in the ADT group regardless of the PC stage (p < 0.05). Multivariate analysis failed to show any significant difference in overall survival between the two groups (p > 0.05). ADT resulted in a significantly higher incidence of OF among patients with localized and regional PC, but the overall survival did not differ between ADT and non-ADT groups. [ABSTRACT FROM AUTHOR]

Objectives: Androgen deprivation therapy (ADT) is used alone or in combination with docetaxel or androgen inhibitors in the initial treatment of metastatic PC (mPC). Enzalutamide is an androgen receptor inhibitor that is used orally and plays a role in different steps of the androgen receptor (AR) signal pathway. The aim of this study is to determine the real life data of patients using enzalutamide for metastatic PC. Methods: 118 patients from totally 6 centers using enzalutamide treatment were included in this retrospective analysis. Clinical information of patients were recorded from patient files or automation records. Results: Median OS was 71 months and median PFS was 5 months (4,1-5,9 months). There was no association of Gleason score with OS and PFS (p=0.5 and p=0.4, respectively). Although those who were metastatic at the time of diagnosis lived longer than those who developed metastases later, the difference was not statistically significant (p=0.9). Likewise, there was no relationship between the time of metastasis development and PFS (p=0.2). There was no difference in OS and PFS between patients with visceral metastasis and those without (p=0.3, p=0.5, respectively). Conclusion: Enzalutamide is an effective and safe agent in accordance with the literature in the patient group included in this study, although some patients may have an unresponsiveness to enzalutamide or develop progression under the enzalutamide treatment. More studies are needed to understand which patient group can benefit more from enzalutamide. [ABSTRACT FROM AUTHOR]

Background. Several novel androgen receptor antagonists have been introduced into the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). We conducted a meta-analysis to evaluate the survival and safety of the combination therapy of novel androgen receptor antagonist and androgen-deprivation therapy (ADT) in patients with mHSPC. Methods. Electronic databases were searched for randomized controlled trials (RCTs) of ADT combined with novel androgen receptor antagonists compared with ADT alone in men with mHSPC. Revman 5.4 and STATA 14.0 were used to performed the meta-analysis, and hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs) were used as the measurement indicators of outcome variables. Results. Six RCTs were eventually identified for meta-analysis. Compared with ADT alone, the combination therapy of novel androgen receptor antagonists and ADT can significantly improve the overall survival (OS) and progression-free survival (PFS), as the pooled HR were 0.66, 95%CI (0.60, 0.72), P < 0.00001 and 0.43, 95%CI (0.34, 0.54), P < 0.00001 , respectively, despite increasing the risk of any serious adverse events (OR: 1.18, 95%CI (1.04, 1.33), P = 0.008). Discussion. This study showed that compared with ADT alone, the combination therapy of novel androgen receptor antagonists and ADT can significantly improve the survival status of mHSPC patients, while it increases the risk of serious adverse events. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether the addition of statins to the new antiandrogens (enzalutamide or abiraterone) affects overall survival in patients with metastatic castration-resistant prostate cancer. Methods: We searched studies in English language including the keywords statins, overall survival, and metastatic castration-resistant prostate cancer, at PubMed® (MEDLINE®), Embase and Cochrane databases. Results: A total of 195 articles were initially identified, but only four met the inclusion criteria and were selected for the meta-analysis. A total of 955 patients, 632 on the new antiandrogens only group, and 323 on the new antiandrogens + statins group, were analyzed. In all four studies the combination therapy (new antiandrogens + statin) was well tolerated, regardless of which new antiandrogens were used. Neither the type of statin nor the doses and duration of use were well specified in the studies. The combination therapy in metastatic castration-resistant prostate cancer was associated with an overall survival improvement, and a 46% reduction in death (hazard ratio of 0.54; 95%CI 0.34-0.87; p<0.01) in multivariate analysis. Conclusion: There seems to be a clinical benefit with the association of statins to the new antiandrogens in patients with metastatic castration-resistant prostate cancer, suggesting longer overall survival with no important collateral effect. However, due to fragility of the studies available in the literature, we are not yet capable of recommending this combination of drugs in the clinical practice. Further randomized prospective studies are warranted to confirm these beneficial outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To identify patients with intermediate-risk prostate cancer (IRPC) benefiting from de-escalation of androgen deprivation therapy (ADT) and/or dose escalated radiation therapy (DERT), we performed a secondary analysis of a phase 3 trial by measuring biochemical failure (BF), distant metastases, prostate cancer-specific mortality, overall survival (OS), and distant metastases-free survival (DMFS) rates according to prognostic intermediate risk factors (IRF).Methods and Materials: The initial trial randomized 600 patients with IRPC to a 3-arm trial with 200 patients per arm, consisting of 6 months of ADT plus 70 Gy radiation therapy (ADT + RT70) versus ADT plus a DERT of 76 Gy (ADT + DERT76) versus DERT of 76 Gy alone (DERT76). We performed an analysis based on IRF: clinical stage, prostate-specific antigen level, Gleason score, percentage of positive biopsy cores (PBC) ≥50%, and Gleason pattern. Patients were allocated to 2 groups: favorable intermediate risk (FIR), defined as patients with only 1 IRF without Gleason pattern 4 + 3 or PBC ≥50%; and unfavorable intermediate risk (UIR), defined as all other patients. BF, distant metastases, prostate cancer-specific mortality, OS, and DMFS were compared between FIR and UIR.Results: The median follow-up was 11.3 years (interquartile range, 10.9-11.7). In the FIR cohort, BF and OS were not significantly different between arms. UIR patients had significantly worse DMFS (hazard ratio [95% confidence interval], 1.61 [1.20-2.15]; P = .026) and OS (1.51 [1.12-2.04]; P = .0495) and a nonsignificant higher cumulative incidence of BF rate (1.55 [0.98-2.47]; P = .08). In UIR patients, a significant improvement in BF was seen in the arms receiving ADT compared to DERT76 alone. On multivariable analysis, Gleason pattern 4 + 3 and prostate-specific antigen >10 ng/mL independently affected BF and OS, regardless of the treatment arm.Conclusions: In IRPC, therapeutic optimization appears possible. To avoid ADT side effects, DERT76 alone appears sufficient in patients harboring only 1 risk factor without Gleason pattern 4 + 3 and PBC ≥50% (FIR). All other UIR patients seem to benefit from ADT + DERT76. [ABSTRACT FROM AUTHOR]

Background: The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC.Methods: ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone-prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone-prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.Findings: 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone-prednisone; 490 to abiraterone-prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0-28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4-27·4) in the apalutamide plus abiraterone-prednisone group versus 16·6 months (13·9-19·3) in the abiraterone-prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58-0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5-58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7-27·5) versus 16·6 months (13·9-19·3; HR 0·70, 95% CI 0·60-0·83; p<0·0001). The most common grade 3-4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone-prednisone and 49 [10%] of 489 receiving abiraterone-prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone-prednisone and 181 (37%) patients receiving abiraterone-prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone-prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone-prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death).Interpretation: Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone-prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC.Funding: Janssen Research & Development. [ABSTRACT FROM AUTHOR]

Introduction: Enzalutamide, apalutamide, and darolutamide have all been approved by Food and Drug Administration to treat high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) since 2018 based on interim results of several phase III clinical trials. Final analyses of long-term overall survival (OS) and adverse events (AEs) results of these trials have been successively published recently. To help clinical practice to precisely select optimal treatment for high-risk nmCRPC patients, we performed a network meta-analysis to indirectly compare the final long-term results among these medications. Methods: PubMed, EMBASE, and Cochrane Libraries were searched for phase III clinical trial that reports OS and AEs results in nmCRPC patients published before January 30, 2021. Primary outcome was OS; secondary outcomes were Time to first chemotherapy, Subsequent antineoplastic therapy rate, and AEs. Firstly, class-level effect was assessed as the second-generation androgen receptor antagonists (SGARAs) were regarded as one whole class compared with placebo through traditional meta-analysis by using Revman 5.4, then a Bayesian network meta-analysis was conducted to give indirect comparison among SGARAs by using R 3.5.3 software. Subgroup analysis of OS was only conducted in the certain subgroups which were available in all included studies. Results: Three eligible studies including 4,104 participants were finally selected. OS was significantly improved by the SGARAs as a class compared with placebo (HR, 0.74; 95% CI, 0.66–0.84). Darolutamide had the highest likelihood of providing best OS (p-score=0.802). SGARAs also significantly delayed the first time to chemotherapy (HR, 0.58; 95% CI, 0.50–0.66). Patients who received darolutamide experienced similar toxicity compared with placebo regarding AEs of grade 3 or higher (OR, 1.3; 95% CI, 1.0–1.7) and serious AEs (OR, 1.3; 95% CI, 0.99–1.6). When compared with darolutamide, enzalutamide caused significantly higher toxicity in terms of any AEs (OR, 2.3; 95% CI,1.5–3.7) and AEs of grade 3 or higher (OR, 1.6; 95% CI, 1.1–2.2), apalutamide caused significantly more AEs of grade 3 or higher (OR, 1.9; 95% CI, 1.4–2.7) and serious AEs (OR, 1.9; 95% CI, 1.3–2.8). Subgroup analysis showed that SGARAs as a group significantly improved OS in ECOG=1 population, although insignificant results were found in these patients from included studies. Conclusions: SGARAs combined with ADT significantly improved OS when compared with ADT alone in high-risk nmCRPC patients. Darolutamide may not only provide best OS but also have the most favorable safety profile among the included SGARAs in high-risk nmCRPC patients. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the recent real‐world use of first‐generation antiandrogens (FGAs) in metastatic castration‐resistant prostate cancer (mCRPC) using a retrospective multicentre cohort study. Patients and Methods: The electronic CRPC Australian Database (ePAD) was interrogated to identify patients with mCRPC. Clinicopathological features, treatment and outcome data, stratified by FGA use, were retrieved and reported through descriptive statistics. Survival analyses were calculated using the Kaplan–Meier method and groups compared using log‐rank tests. Factors influencing overall survival (OS) were analysed using Cox proportional hazards regression model. Results: We identified 634 patients with mCRPC, enrolled in ePAD between January 2016 and March 2019, including 322 (51%) who received FGAs. The median follow‐up was 21.9 months. Patients treated with FGAs were more likely to have lower International Society of Urological Pathologists (ISUP) grade group (P = 0.04), longer median time to CRPC (25.6 vs 16.0 months, P < 0.001), and were less likely to have visceral metastases (5.0% vs 11.2%, P = 0.005) or to have received upfront docetaxel (P < 0.001). A ≥50% reduction from pre‐treatment prostate‐specific antigen (PSA) level (PSA50 response) during FGA treatment occurred in 119 (37%) patients and was independently associated with improved OS (hazard ratio 0.233, P < 0.001). Prior FGA treatment did not significantly influence the selection of subsequent life‐prolonging treatments for mCRPC or their PSA50 response rates. Conclusion: In our present cohort, FGAs were commonly used in lower‐risk mCRPC and their use did not significantly influence the choice or duration of subsequent systemic therapy. A PSA50 response to FGA therapy was an independent favourable prognostic marker associated with improved OS. [ABSTRACT FROM AUTHOR]

Objective: To interrogate the National Veterans Health Administration (VA) database to determine if beta-blocker use at time of initiation of androgen therapy deprivation (ADT) would result in improved oncological outcomes in advanced prostate cancer (PCa).Methods: All men diagnosed with high risk PCa (PSA >20) from 2000-2008 who were on ADT ≥ 6 months were identified. Patients receiving ADT concurrently with primary radiation therapy were excluded. Pharmacy data was interrogated for all beta-blockers, but then focused on the selective beta-1 blocker metoprolol. Cox proportional hazards ratios were calculated for overall survival (OS), PCa specific survival (CSS) and skeletal related events (SREs).Results: In 39,198 patients with high risk PCa on ADT, use of any beta-blocker was not associated with improvement in OS, CSS, or SREs. Further analyses focusing on metoprolol found that 10,224 (31.9%) had used metoprolol while 21,834 had no beta-blocker use. Multivariable analysis with Inverse Propensity Score Weighting, adjusted for factors including PSA, Gleason score, and duration ADT, found that utilization of metoprolol was not associated with improvement in OS (hazard ratio [HR] 0.97, P = .19), CSS (HR 0.94, P = .23) or SREs (HR 0.98, P = .79).Conclusion: In this large cohort, metoprolol use in conjunction with ADT in high risk PCa was not associated with improvement in OS, CSS, or risk of SRE. In contrast to a recent smaller clinical study, our data strongly suggests no cancer specific benefit to beta-blocker use in advanced PCa. [ABSTRACT FROM AUTHOR]

Background: Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer.Methods: We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 μg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (<80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment.Findings: Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged <80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged <80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups).Interpretation: The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient.Funding: None. [ABSTRACT FROM AUTHOR]

Abiraterone acetate (ABI) and enzalutamide (ENZ) are considered to be clinically relevant comparators among chemotherapy-naive patients with castration-resistant prostate cancer. No clinical trials comparing overall survival with ABI versus ENZ in a head-to-head approach have been published so far. A few observational studies with low power suggested a potential benefit of ENZ. We used the French National Health Data System to compare overall survival of new users of ABI and ENZ among chemotherapy-naive patients with castration-resistant prostate cancer in 2014–2017, followed through 2018 (the SPEAR cohort, a 2014–2018 cohort study). With an intent-to-treat approach, a survival analysis was performed, estimating hazard ratios for overall survival with the inverse probability weighted Cox model method. Among 10,308 new users, 64% were treated with ABI and 36% with ENZ. The crude mortality rate was 25.2 per 100 person-years (95% confidence interval (CI): 24.4, 26.0) for ABI and 23.7 per 100 person-years (95% CI: 22.6, 24.9) for ENZ. In the weighted analysis, ENZ was associated with better overall survival compared with ABI (hazard ratio = 0.90 (95% CI: 0.85, 0.96) with a median overall survival of 31.7 months for ABI and 34.2 months for ENZ). When restricting to 2015–2017 new users, the effect estimate shifted up to a hazard ratio of 0.93 (95% CI: 0.86, 1.01). [ABSTRACT FROM AUTHOR]

As the most common solid tumor diagnosed among men, prostate cancer is responsible for the death of a remarkable number of men worldwide every year. The present study was carried out in order to figure out the survival patterns and the effective variables in patients with hormone refractory prostate cancer. Using a retrospective cohort design with a nested case-control study approach, the present study was carried out on 150 patients with prostate cancer at Hiwa Cancer Hospital located in Sulaimania, the Iraqi Kurdistan in 2014. The patients were assigned into a case group (who developed resistance to androgen deprivation therapy) and a control group (who did not develop resistance to androgen deprivation therapy within the first three years of prostate cancer treatment). The required data were collected through a researcher-designed questionnaire and using the patients' hospital records. Most of the patients aged between 65 to 80 years. According to the results, the highest survival probability belonged to the age group 60-80, while the lowest was related to those aged less than 60 years, and there was no significant relationship between age groups and overall survival (p>0.05). Prostate cancer is more likely to develop in males aged 65 to 80 year. They patients' overall survival is not correlated with their age, while there is a correlation between the stage of their tumors and their overall survival. The patients' their progression-free survival was found to be significantly affected by their age and histopathology, while the stage of their tumors was not in a significant correlation with their progression-free survival. [ABSTRACT FROM AUTHOR]

Background: Androgen deprivation therapy (ADT) remains a standard of care in metastatic prostate cancer. Recent prospective trials have explored addition of chemotherapy to ADT. We retrospectively examined overall survival in metastatic prostate cancer patients treated with ADT, chemotherapy plus ADT (C + ADT), or observation from 2004 to 2010 using National Cancer Database data. Methods: Using the National Cancer Database, 21,977 patients with metastatic prostate cancer diagnosed from 2004 to 2010 were identified. Multivariate logistic regression, Kaplan-Meier survival analysis and Cox proportional hazards regression modeling were implemented, with overall survival as the primary endpoint. Results: Five-year overall survival was 13.6% in patients aged ≥ 75 years vs. 30.1% (age 65–74) and 34.5% (age 18–64). Subgroup analysis of age-based cohorts (<65 and ≥65 years) showed poor overall survival for C + ADT vs. ADT alone, both in younger (HR 1.35, 95% CI 1.21–1.50; p < 0.0001) as well as older (HR 1.21, 95% CI 1.08–1.34; p = 0.0006) populations. Younger patients had no significant difference in overall survival for observation vs. ADT (HR 0.99, 95% CI 0.92–1.08; p = 0.9121). Besides age, other factors impacting overall survival included race, rural/urban settings, comorbidity score, income, PSA and radiation. Discussion: Younger patients had no significant difference in overall survival between observation or ADT. This implies a group of younger patients in whom ADT does not confer any overall survival benefit. Future clinical trials with genetic and biologic markers are needed to delineate which subgroups would not benefit from C + ADT or ADT alone. This is of utmost clinical importance given the negative impact of ADT on quality of life and comorbidities. [ABSTRACT FROM AUTHOR]

Purpose: Overall survival (OS) has traditionally been the primary endpoint to evaluate drug efficiency in oncology but is often limited by the long observation period and high cost. The aims of this study were to perform a comprehensive meta-analysis at a clinical trial level to investigate the potential surrogate endpoints of OS in patients with castration-resistant prostate cancer (CRPC), and to predict OS based on the relationships associated with the potential surrogate endpoints. Methods: A systematic literature search was conducted in the PubMed database up to August 2018. Correlations between OS and potential surrogate endpoints were determined by linear regression analysis weighted by the square roots of sample size. Simulations were conducted to assess the effect of covariates on the relationships between OS and surrogate endpoints. Results: A total of 233 studies including clinical trials and real-world data were included in our dataset. The correlations between median OS and potential surrogate endpoints for androgen-targeting therapy (R2 = 0.58–0.92) were generally stronger than those for taxane chemotherapy (R2 = 0.37–0.71). Median radiographic progression-free survival (rPFS) showed the strongest correlations with median OS (R2 = 0.94) in patients treated with novel androgen-targeting therapy. Conclusion: The meta-analysis demonstrated that rPFS might serve as a potential surrogate endpoint of OS and offer opportunity to facilitate the interim analyses and decision-making during the early stage of clinical trials for androgen-targeting agents. [ABSTRACT FROM AUTHOR]

In the phase 3 ARAMIS study (NCT02200614), darolutamide significantly improved metastasis-free survival in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Following the primary analysis, the study was unblinded, and placebo recipients were permitted to cross over to open-label darolutamide. Despite crossover, darolutamide significantly improved overall survival (OS). We conducted sensitivity analyses to estimate the effect of placebo–darolutamide crossover on OS. Patients with nmCRPC were randomised to oral darolutamide 600 mg twice daily (n = 955) or placebo (n = 554). Prespecified (rank-preserving structural failure time [RPSFT] and iterative parameter estimation [IPE]) and post hoc (OS-adjusted censoring and inverse probability of censoring weighting [IPCW], with weightings for baseline testosterone and prostate-specific antigen) sensitivity analyses were conducted. After unblinding, 170 of 554 placebo recipients (30.7%) crossed over to darolutamide. At the final OS intention-to-treat analysis (median 11.2 months after unblinding), darolutamide significantly improved OS by 31% versus placebo (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.53–0.88; P = 0.003). The benefit increased in the analyses adjusting for crossover is as follows: RPSFT HR 0.68, 95% CI 0.51–0.90; P = 0.007; IPE HR 0.66, 95% CI 0.51–0.84; P < 0.001; OS-adjusted censoring HR 0.59, 95% CI 0.45–0.76; IPCW HR 0.63, 95% CI 0.48–0.81. The favourable safety profile of darolutamide was maintained, including in crossover patients. After adjusting for crossover, darolutamide reduced the risk of death by up to 41% in patients with nmCRPC. The effect of darolutamide on OS may have been underestimated in the original intention-to-treat analysis. • Darolutamide significantly improved metastasis-free survival (MFS) versus placebo in men with nmCRPC. • After the MFS analysis, 170 placebo recipients (31%) crossed over to open-label darolutamide. • In the final analysis, darolutamide reduced the risk of death by 31% (HR 0.69) versus placebo. • Sensitivity analyses indicate a risk reduction for death of up to 41% if crossover had not occurred. • These analyses confirm darolutamide as an effective early treatment option in nmCRPC. [ABSTRACT FROM AUTHOR]

Whether disease burden in patients with metastatic castration-sensitive prostate cancer (mCSPC) predicts treatment outcomes is unknown. We assessed apalutamide treatment effect in TITAN patients with mCSPC by disease volume, metastasis number and timing of metastasis presentation. These protocol-defined and post hoc analyses of the phase III randomised TITAN study evaluated clinical outcomes in patients receiving 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy (ADT). Subgroups were defined by volume (high: visceral and ≥1 bone metastases or ≥4 bone lesions with ≥1 beyond vertebral column/pelvis), development of metastases per conventional imaging (synchronous: at initial diagnosis; metachronous: after localised disease) and oligometastases (≤5 bone-only metastases) or polymetastases (>5 in bone ± other locations or ≤5 in bone plus other locations). Overall survival (OS), radiographic or second progression-free survival, and time to prostate-specific antigen progression or castration resistance were assessed using Cox proportional hazards models. Of 1052 patients, 63%, 81%, 54%, 27%, 5.7%, and 8.0% had high-volume, synchronous, synchronous/high-volume, synchronous/low-volume, metachronous/high-volume, and metachronous/low-volume disease, respectively. The OS benefit favoured apalutamide plus ADT versus ADT alone in synchronous/high-volume (hazard ratio = 0.68 [95% confidence interval: 0.53–0.87]; p = 0.002), synchronous/low-volume (0.65 [0.40–1.05]; p = 0.08), metachronous/high-volume (0.69 [0.33–1.44]; p = 0.32) and metachronous/low-volume (0.22 [0.09–0.55]; p = 0.001) subgroups. Apalutamide improved other clinical outcomes regardless of subgroup, with similar safety profiles. Most favourable outcomes were observed in oligometastatic disease. TITAN patients derived a robust benefit with apalutamide plus ADT regardless of disease volume and timing of metastasis presentation without differences in safety, supporting early apalutamide intensification in mCSPC. NCT02489318. • Apalutamide plus ADT improved outcomes in mCSPC regardless of disease burden. • Apalutamide improved outcomes in poor-prognosis subgroups. • Patients with oligometastatic bone-only disease benefitted most from apalutamide. • Apalutamide plus ADT was safe regardless of disease burden. [ABSTRACT FROM AUTHOR]

Highlights • Many real-world metastatic castration-resistant cancer patients are >75 years old. • Age does not influence treatment duration or overall survival. • Rates of adverse events of treatment do not differ with age. • Elderly patients with ECOG 0 and/or G8 score >14 have longer overall survival. Abstract Background Abiraterone acetate and enzalutamide are standard treatments for chemotherapy-naive metastatic castration-resistant prostate cancer (CN-mCRPC). The purpose of this study was to evaluate the effectiveness and safety of these medications in elderly (≥ 75 years old) compared with young CN-mCRPC patients in a real-world clinical setting. Secondarily, we explored the survival prognostic value of different anatomo-clinical factors in elderly group. Methods In this retrospective observational multicentre study, we included 134 consecutive CN-mCRPC patients, 64 young and 70 elderly men, who had received AA or Enz. Results We did not find significant differences in treatment duration [16.6 months, (95% CI 9–24.2 months) vs. 16.8 months (95% CI: 6.3–27.2 months); p = 0.926] and overall survival [median not reached vs. 23.3 months (95% CI 10.2–36.3 months); p = 0.131] between the young and elderly groups. In elderly group, the only predictors of overall survival with AA or Enz were good ECOG performance status and high G8 score. Adverse events of grade ≥3 was similar in elderly group (12.9%) and in the young group (15.6%). Treatment was discontinued due to AEs in 6.3% of young group and 18.6% of elderly group. Conclusions Effectiveness and safety of treatment of CN-mRCPC with Abiraterone acetate and enzalutamide were similar in older and younger patients, although treatment discontinuation due to AEs was more frequent in the older age group. In addition to ECOG PS, assessment using specific geriatric scales as G8 screening tool could help to identify patients aged ≥75 who would most benefit from treatment with new-generation hormone therapy. [ABSTRACT FROM AUTHOR]

Background Combined androgen blockade (CAB) is a promising treatment modality for prostate cancer (PCA). In the present meta-analysis, we compared the efficacy and safety of first-line CAB using an antiandrogen (AA) with castration monotherapy in patients with advanced PCA. Methods PubMed, EMBASE, Cochrane, and Google Scholar were searched for randomized controlled trials (RCTS) published through 12 December 2016. Hazard ratios (HRS) with 95% confidence intervals (CIS) were determined for primary outcomes: overall survival (OS) and progression-free survival (PFS). Subgroup analyses were performed for Western compared with Eastern patients and use of a nonsteroidal AA (NSAA) compared with a steroidal AA (SAA). Results Compared with castration monotherapy, CAB using an AA was associated with significantly improved OS (n = 14; HR: 0.90; 95% CI: 0.84 to 0.97; p = 0.003) and PFS (n = 13; HR: 0.89; 95% CI: 0.80 to 1.00; p = 0.04). No significant difference in OS (p = 0.71) and PFS (p = 0.49) was observed between the Western and Eastern patients. Compared with castration monotherapy, CAB using a NSAA was associated with significantly improved OS (HR: 0.88; 95% CI: 0.82 to 0.95; p = 0.0009) and PFS (HR: 0.85; 95% CI: 0.73 to 0.98; p = 0.007)—a result that was not achieved with CAB using a SAA. The safety profiles of CAB and monotherapy were similar in terms of adverse events, including hot flushes, impotence, and grade 3 or 4 events, with the exception of risk of diarrhea and liver dysfunction or elevation in liver enzymes, which were statistically greater with CAB using an AA. Conclusions Compared with castration monotherapy, first-line CAB therapy with an AA, especially a NSAA, resulted in significantly improved OS and PFS, and had an acceptable safety profile in patients with advanced PCA. [ABSTRACT FROM AUTHOR]

In patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the Androgen Receptor Antagonizing Agent for Metastasis-free Survival (ARAMIS) trial, darolutamide significantly improved median metastasis-free survival by nearly 2 years and reduced the risk of death by 31% versus placebo, with a favourable safety/tolerability profile. This post hoc analysis of ARAMIS evaluated efficacy and safety in patients by number of comorbidities and concomitant medications. Patients with nmCRPC were randomised 2:1 to darolutamide (n = 955) or placebo (n = 554) while continuing androgen-deprivation therapy. Overall survival (OS) and treatment-emergent adverse events (TEAEs) were evaluated in subgroups by median numbers of ongoing comorbidities and concomitant medications. HRs were determined from univariate analysis using Cox regression. Median numbers of comorbidities and concomitant medications were 6 and 10, respectively, with 41.6% of patients having >6 comorbidities and 48.8% taking >10 concomitant medications. For patients with ≤ 6 and >6 comorbidities, darolutamide increased OS versus placebo (hazard ratio [HR] 0.65 and 0.73, respectively), and this benefit was consistent for cardiovascular, metabolic, and other comorbidities (HR range: 0.39–0.88). For patients taking ≤ 10 and >10 concomitant medications, increased OS was also observed with darolutamide versus placebo (HR 0.76 and 0.66, respectively), and the benefit was consistent across medication classes (HR range: 0.45–0.80). Incidences of TEAEs and TEAEs leading to treatment discontinuation with darolutamide were similar to placebo across subgroups by numbers of comorbidities and concomitant medications. The OS benefit and safety of darolutamide remained consistent with that observed in the overall ARAMIS population, even in patients with high numbers of comorbidities or concomitant medications. NCT02200614. Darolutamide increased overall survival versus placebo, and incidences of most adverse events were similar between treatments in patients with ≤ 6 or >6 comorbidities and those taking ≤ 10 or >10 concomitant medications. [Display omitted] • Patients with nmCRPC in ARAMIS had a substantial comorbidity burden. • Darolutamide provided consistent survival benefit across comorbidity subgroups. • Darolutamide improved survival independent of the number of concomitant medications. • Safety of darolutamide in these subgroups was consistent with overall population. [ABSTRACT FROM AUTHOR]

Objectives: To assess treatment patterns and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy or antiandrogen therapy. Patients and Methods: Patients initiating first-line antiandrogen therapy (abiraterone, enzalutamide) or chemotherapy (taxane) between October 2012 and September 2014 were retrospectively identified in the US Veterans Health Administration database. The impact of antiandrogen therapy vs chemotherapy on overall survival (OS) and time to discontinuation was assessed using Cox proportional hazard models, adjusting for prior androgen deprivation therapy (ADT) duration and available prognostic factors. Results: Overall, 1445 patients were evaluable, of whom 1108 received antiandrogen therapy and 337 received chemotherapy (docetaxel). On multivariable analysis and propensity score analysis, the OS times for antiandrogen therapy vs chemotherapy were not significantly different (hazard ratio [HR] 1.041, 95% confidence interval (CI) 0.853-1.270, P = 0.694, and HR 1.047, 95% CI 0.861-1.273, P = 0.644, respectively). Time to discontinuation was shorter for chemotherapy vs antiandrogen therapy (HR 2.339, 95% CI 1.969-2.779; P < 0.001). Prior ADT duration above the median was associated with longer OS (HR 0.566, 95% CI 0.464-0.690; P < 0.001) and time to discontinuation (HR 0.831, 95% CI 0.699-0.988; P = 0.036) in the antiandrogen therapy cohort and not the chemotherapy cohort, while prior ADT duration below the median was associated with higher prostate specific antigen (PSA) response rate in the chemotherapy vs antiandrogen therapy cohort (61.5% vs 51.1%; P = 0.024). The treatment-free interval after discontinuation was longer after first-line chemotherapy vs antiandrogen therapy (mean 53 vs 39 days; P = 0.030). Conclusion: After adjusting for key prognostic factors in this large mCRPC dataset, the OS was similar for first-line chemotherapy vs antiandrogen therapy despite shorter time to discontinuation with chemotherapy and longer treatmentfree interval after first-line chemotherapy. These hypothesisgenerating data also suggest that duration of prior ADT may assist in the selection of patients for chemotherapy vs antiandrogen therapy. [ABSTRACT FROM AUTHOR]

Introduction: Enzalutamide - a non-steroidal second-generation antiandrogen - represents an active treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC) in both chemotherapy-naïve and docetaxel-pretreated settings, based on the demonstration of improved overall survival over placebo in two large phase III trials.Areas Covered: The therapeutic landscape of mCRPC, narrowed to docetaxel until recently, encompasses now several treatments of a different nature (including androgen receptor targeting agents, taxanes, radiometabolic therapy, and immunotherapy), improving considerably the patients prognosis. However, direct comparisons between these agents still lack, raising the question of the optimal sequence of treatment. Expert commentary: We described in detail available data on clinical efficacy and safety of enzalutamide in different clinical settings (chemotherapy-naïve and -pretreated mCRPC patients), analyzing patients characteristics, the effects of enzalutamide on major clinical outcomes and its impact on patients quality of life. Finally, we briefly overviewed ongoing clinical trials evaluating potential active combinations, cross-resistance with other compounds, sequential strategies, and possible prognostic or predictive biomarkers. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most prevalent cancer among men in the Western world and a leading cause of cancer-related death among men. Within 5 years of initial diagnosis, approximately 10-20% of men will progress to metastatic castration-resistant prostate cancer (mCRPC). Often characterized by increased prostate-specific antigen and androgen receptor (AR) activity despite castrate levels of testosterone, mCRPC has a poor prognosis and causes significant deterioration in quality of life. Enzalutamide is an AR inhibitor approved to treat mCRPC in both post- and pre-chemotherapy settings on the basis of results from two phase III randomized, placebo-controlled trials, AFFIRM and PREVAIL, respectively. Enzalutamide significantly prolonged overall survival (hazard ratio (HR), AFFIRM 0.63, 95% confidence interval (CI) 0.53-0.75, P < 0.001; PREVAIL 0.71, 95% CI 0.60-0.84, P < 0.001) and radiographic progression (HR, AFFIRM 0.40, 95% CI 0.35-0.47, P < 0.001; PREVAIL 0.19, 95% CI 0.15-0.23, P < 0.001), and significantly improved quality of life. With an acceptable safety profile, enzalutamide is one of several emerging alternative options for men with mCRPC. Studies are ongoing to explore potential benefits of enzalutamide in earlier stages of prostate cancer and in breast cancer. [ABSTRACT FROM AUTHOR]

What Is This Summary About?: This is a summary of a publication about the ARASENS trial, which was published in the New England Journal of Medicine in February 2022. The trial includes 1,306 men with a type of prostate cancer called metastatic, hormone-sensitive prostate cancer (also called mHSPC). In the trial, researchers wanted to learn if combining a treatment called darolutamide (also known by the brand name Nubeqa®) with two other medicines called androgen deprivation therapy (also called ADT) and docetaxel (brand name Taxotere®) could help treat patients with mHSPC better than placebo plus ADT and docetaxel. ADT with docetaxel is a treatment used for patients with mHSPC. Darolutamide is an approved treatment for a different type of prostate cancer called non-metastatic, castration-resistant prostate cancer (also called nmCRPC).What Were the Results?: The trial results showed that combining darolutamide with ADT and docetaxel increased the chance of survival and lowered the risk of death by 32.5% compared to combining ADT and docetaxel with placebo instead. Compared to patients who received the placebo, patients who received darolutamide had a delay in: their cancer becoming castration-resistant worsening pain having cancer-related bone fractures or related symptoms needing additional therapies for cancer The percentage of trial patients who had medical problems during the trial, also called adverse events, was similar between trial patients who received darolutamide and those who received the placebo.What Do the Results Of the Study Mean?: Combining darolutamide with ADT and docetaxel helped treat trial patients with mHSPC better than placebo with ADT and docetaxel. Darolutamide in combination with ADT and docetaxel could be a treatment option for patients with mHSPC. Patients should always talk to their doctors and nurses before making any decisions about their treatment. This summary also includes perspectives on the ARASENS trial and prostate cancer from 3 members of the patient community. ClinicalTrials.gov NCT number: NCT02799602. [ABSTRACT FROM AUTHOR]