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Objective: To describe the baseline symptom burden(SB) experienced by patients(pts) with recurrent ovarian cancer(ROC) prior and associations with progression free survival (PFS) and overall survival (OS)., Methods: We analysed baseline SB reported by pts. with platinum resistant/refractory ROC (PRR-ROC) or potentially‑platinum sensitive ROC receiving their third or greater line of chemotherapy (PPS-ROC≥3) enrolled in the Gynecologic Cancer InterGroup - Symptom Benefit Study (GCIG-SBS) using the Measure of Ovarian Symptoms and Treatment concerns (MOST). The severity of baseline symptoms was correlated with PFS and OS., Results: The 948 pts. reported substantial baseline SB. Almost 80% reported mild to severe pain, and 75% abdominal symptoms. Shortness of breath was reported by 60% and 90% reported fatigue. About 50% reported moderate to severe anxiety, and 35% moderate to severe depression. Most (89%) reported 1 or more symptoms as moderate or severe, 59% scored 6 or more symptoms moderate or severe, and 46% scored 9 or more symptoms as moderate or severe. Higher SB was associated with significantly shortened PFS and OS; five symptoms had OS hazard ratios larger than 2 for both moderate and severe symptom cut-offs (trouble eating, vomiting, indigestion, loss of appetite, and nausea; p < 0.001)., Conclusion: Pts with ROC reported high SB prior to starting palliative chemotherapy, similar among PRR-ROC and PPS-ROC≥3. High SB was strongly associated with early progression and death. SB should be actively managed and used to stratify patients in clinical trials. Clinical trials should measure and report symptom burden and the impact of treatment on symptom control., Competing Interests: Conflict of interest statement FR acknowledges travel grant from Pfizer. Y-CL acknowledges institutional research grant from Beigene, honoraria from Astra Zeneca for educational event and received honoraria from GSK for participation in advisory board. MF acknowledges institutional grants from Astra Zeneca, Beigene, Novartis; received honoraria from Astra Zeneca, GSK, MSD; consulting fees from Astra Zeneca, Novartis, GSK, Incyclix. JL acknowledges grants from Astra Zeneca, MSD/Merck; advisory board for Astra Zeneca, Clovis Oncology, GSK, Artios Pharma, MSD/Merck, VBL Therapeutics, BMS, Nuvation, Ellipses, Immagene, Incyte, Immunogen; educational events for Astra Zeneca, MSD/Merck, GSK, Eisai, Neopharm, and data safety monitoring board for Mersana. AO acknowledges data safety monitoring board for Morphosys, Astra Zeneca, BMS, and uncompensated leadership role for Ozmosis Research where he is CEO and Board member. FH acknowledges grants from GSK, Astra Zeneca, MSD, PharmaMar, Immunogen, consulting fees from Immunogen, MSD, Astra Zeneca; honoraria from GSK, Astra Zeneca, MSD, Pharma Mar; and has been on data safety monitoring boards for MSD, GSK and Astra Zeneca. JB acknowledges grants from Tesaro, Eisai, Immunogen, Karyopharm. MS acknowledges institutional grants from Astellas, Amgen, Astra Zeneca, Bionomics, BMS, Celgene, Medivation, Merck, Sharp and Dohme, Pfizer, Roche and Sanofi. MK, RO, EA-L, FJ, M-CK, YY, DB and AL declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have revolutionised the management of patients with high-grade serous and endometrioid ovarian cancer demonstrating significant improvements in progression-free survival. Whilst the greatest benefit is seen with BRCA1/2 mutant cancers, it is clear that the benefit extends beyond this group. This sensitivity is thought to be due to homologous recombination deficiency (HRD), which is present in up to 50% of the high-grade serous cancers. Several different HRD assays exist, which fall into one of three main categories: homologous recombination repair (HRR)-related gene analysis, genomic "scars" and/or mutational signatures, and real-time HRD functional assessment. We review the emerging data on HRD as a predictive biomarker for PARP inhibitors and discuss the merits and disadvantages of different HRD assays. [ABSTRACT FROM AUTHOR]

BACKGROUND: The authors performed a meta‐analysis to better quantify the benefit of maintenance poly(ADP‐ribose) polymerase inhibitor (PARPi) therapy to inform practice in platinum‐sensitive, recurrent, high‐grade ovarian cancer for patient subsets with the following characteristics: germline BRCA mutation (gBRCAm), somatic BRCA mutation (sBRCAm), wild‐type BRCA but homologous recombinant‐deficient (HRD), homologous recombinant‐proficient (HRP), and baseline clinical prognostic characteristics. METHODS: Randomized trials comparing a PARPi versus placebo as maintenance treatment were identified from electronic databases. Treatment estimates of progression‐free survival were pooled across trials using the inverse variance weighted method. RESULTS: Four trials included 972 patients who received a PARPi (olaparib, 31%; niraparib, 35%; or rucaparib, 34%) and 530 patients who received placebo. For patients who had germline BRCA1 mutation (gBRCAm1) (N = 471), the hazard ratio (HR) was 0.29 (95% CI, 0.23‐0.37); for those who had germline BRCA2 mutation (gBRCAm2) (N = 236), the HR was 0.26 (95% CI, 0.17‐0.39); and, for those who had sBRCAm (N = 123), the HR was 0.22 (95% CI, 0.12‐0.41). The treatment effect was similar between the gBRCAm and sBRCAm subsets (P =.48). In patients who had wild‐type BRCA HRD tumors (excluding sBRCAm; N = 309), the HR was 0.41 (95% CI, 0.31‐0.56); and, in those who had wild‐type BRCA HRP tumors (N = 346), the HR was 0.64 (95% CI, 0.49‐0.83). The relative treatment effect was greater for the BRCAm versus HRD (P =.03), BRCAm versus HRP (P <.00001), and HRD versus HRP (P <.00001) subsets. There was no difference in benefit based on age, response after recent chemotherapy, and prior bevacizumab. CONCLUSIONS: In platinum‐sensitive, recurrent, high‐grade ovarian cancer, maintenance PARPi improves progression‐free survival for all patient subsets. PARPi therapy has a similar magnitude of benefit for sBRCAm and gBRCAm. Although patients with BRCAm derive the greatest benefit, the absence of a BRCAm or HRD could not be used to exclude patients from maintenance PARPi therapy. BRCA mutation status is able to predict for the magnitude of PARP inhibitor benefit in platinum‐sensitive recurrent high‐grade ovarian tumor. However, the absence of a BRCA mutation or homologous recombinant deficiency in high‐grade ovarian tumor cannot be used to exclude patients from such therapy. [ABSTRACT FROM AUTHOR]

Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach.Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival [OS] > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat.Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm.Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases. [ABSTRACT FROM AUTHOR]

Ovarian cancer patients are usually diagnosed at an advanced stage, experience recurrence after platinum-based chemotherapy, and eventually develop resistance to chemotherapy. Overall survival (OS), which has improved in recent years as more active treatments have been incorporated into patient care, is regarded as the most clinically relevant endpoint in ovarian cancer trials. However, although there remains a significant need for new treatments that prolong OS further without compromising quality of life, it has become increasingly difficult to detect an OS benefit for investigational treatments because of the use of multiple lines of chemotherapy to treat ovarian cancer. Progression-free survival (PFS), which measures the time to disease progression or death, is unaffected by postprogression therapies but does not evaluate the long-term impact of investigational treatments on tumor biology and responses to future therapies. Recent clinical trials of targeted agents in relapsed ovarian cancer have shown improvements in PFS but not OS, and this is possibly reflective of the long postprogression survival (PPS) period associated with this disease. Intermediate endpoints such as the time to second disease progression or death and the time to second subsequent therapy or death may provide supportive evidence for clinically meaningful PFS improvements and may be used to determine whether these improvements persist beyond the first disease progression and throughout subsequent lines of therapy. For clinical trials that have settings with a long PPS duration and/or involve multiple rounds of postprogression therapy, a primary endpoint of PFS supported by intermediate clinical endpoints and OS may provide a more comprehensive approach for evaluating efficacy. Cancer 2015;121:1737-1746. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival.Methods: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients.Findings: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]).Interpretation: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients.Funding: AstraZeneca and Merck. [ABSTRACT FROM AUTHOR]

Abstract Objective In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease. Methods Patients with stage IIB–IV or high-risk (grade 3/clear-cell) stage I–IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB–IV population (European indication) was performed. Results The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval [CI], 0.59–0.99) in 411 patients with stage IIIB–IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69–0.95) in 749 patients with stage IIIB–IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described 'high-risk' subgroup. Safety results in analyzed subgroups were consistent with the overall population. Conclusions Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with >1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored. Highlights • Post hoc analyses of ICON7 explored bevacizumab by stage and extent of residual disease after upfront surgery for OC. • The progression-free survival (PFS) benefit from bevacizumab was seen consistently in all subgroups explored. • The PFS hazard ratio was 0.77 (95% CI, 0.59–0.99) in 411 patients with stage IIIB–IV disease and no visible residuum. • No OS difference was detected overall or in any subgroup except the previously reported 'high-risk' subgroup. • Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. [ABSTRACT FROM AUTHOR]

Objectives: The OPINION study (NCT03402841) demonstrated the activity of maintenance olaparib in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSR OC) without a germline BRCA1 / BRCA2 mutation (non-g BRCA m), with an overall median progression-free survival (PFS) of 9.2 months (mo) (Poveda et al. ASCO 2021). We further explored clinical and molecular characteristics in pts with long-term (LT) and short-term (ST) PFS. Methods: Pts with non-g BRCA m PSR OC and ≥2 prior lines of platinum-based chemotherapy (PBC) incomplete/partial response (CR/PR) to their last PBC received maintenance olaparib (300 mg bid) until progression/unacceptable toxicity. Here, pts were grouped by time from the first dose until disease progression (RECIST v1.1) or death: >18 mo for the LT group and <4 mo for the ST group (chosen based on radiologic scan timings and follow up). Pts who discontinued the study >18 mo after the first dose were also in the LT group. Samples were analyzed using the Myriad myChoice HRD plus and BRACAnalysis CDx assays. Molecular analyses included: tumor BRCA m (t BRCA m); somatic BRCA m (s BRCA m), defined as the presence of a t BRCA m and no g BRCA m; homologous recombination deficiency (HRD), defined as a genomic instability score ≥42 and/or t BRCA m; homologous recombination repair (HRR) gene mutations, excluding BRCA m (non -BRCA HRRm), based on a prespecified 13-gene panel; and TP53 mutation status. Results: Of 279 pts in OPINION, 67 (24%) and 65 (23%) had LT and ST PFS, respectively. At diagnosis, 45/67 pts (67%) in the LT group had FIGO stage III and 15 (22%) had stage IV disease; 47/65 (72%) in the ST group had stage III and 12 (18%) had stage IV disease. Median (range) prior PBC regimens was 2 (2-5) and 2 (2-6) in the LT and ST groups, respectively. About 34/67 (51%) and 12/65 (18%) pts achieved CR to their last PBC, and 33/67 (49%) and 52/65 (80%) had PR in the LT and ST groups, respectively; 48/67 (72%) and 42/65 (65%) had a platinum-free interval of ≥12 mo in the LT and ST groups, respectively. Fifteen out of 67 (22%) and 5/65 pts (8%) were found to have a t BRCA m in the LT and ST groups, respectively; 47/67 (70%) and 25/65 pts (40%) had HRD-positive tumors. Fifteen (22%) and 5 (8%) pts had a non- BRCA HRRm in the LT and ST groups, respectively, although 65% of pts with a non- BRCA HRRm had HRD-positive tumors. Twenty-five (37%) and 32 (49%) had TP53 -disruptive mutations in the LT and ST groups, respectively. Overlap between t BRCA m, HRD, non- BRCA HRRm (including most frequently mutated genes), and TP53 mutations is shown in the Figure. Conclusions: Pts with LT PFS (>18 mo) in OPINION more commonly had HRD-positive tumors, with or without a t BRCA m, than pts with ST PFS (<4 mo), consistent with results showing longer PFS among pts with HRD-positive tumors in the overall population. A higher proportion of pts with LT than ST PFS achieved CR to their last PBC. However, pts could achieve LT PFS regardless of clinical and molecular factors, reinforcing the benefit of maintenance PARP inhibition in non-g BRCA m PSR OC. [ABSTRACT FROM AUTHOR]