Michael L. Friedlander

Ovarian sex cord-stromal tumors are rare and include adult granulosa cell tumors, juvenile granulosa cell tumors, and Sertoli-Leydig cell tumors. Adult granulosa cell tumors the most prevalent malignant ovarian sex cord stromal tumors are the focus of the review which synthesizes published data to highlight the diagnostic challenges and the controversies surrounding the management of adult granulosa cell tumors, juvenile granulosa cell tumors, and Sertoli-Leydig cell tumors. Adult granulosa cell tumors have frequently been misdiagnosed, with up to 30% of cases reassigned after a contemporary review of historical cases, which could affect the interpretation of older studies. Diagnostic accuracy improved in 2009 following the identification of a somatic FOXL2 c.402C>G missense point in almost all adult granulosa cell tumors. Surgery is the mainstay of treatment at diagnosis and recurrence, and fertility-sparing surgery is recommended for younger patients with stage 1 ovarian sex cord-stromal tumors. The role of adjuvant chemotherapy in stage I high-risk adult granulosa and Sertoli-Leydig cell tumors remains controversial, with guidelines providing varied and conflicting recommendations based on limited evidence. Surveillance strategies, including the frequency of follow-up, duration of surveillance, sensitivity, and specificity of tumor markers, and the timing and nature of imaging, are debatable. We reviewed the evolution of systemic therapy for ovarian sex cord-stromal tumors over the last 4 decades and raised questions regarding the choice of chemotherapy regimens and evidence to support adjuvant chemotherapy. The efficacy of endocrine therapy in adult granulosa cell tumors is contentious, and most studies are retrospective with variable criteria to define response and clinical benefit. The available data are discussed, including trials in progress. In conclusion, the management of ovarian sex cord-stromal tumors requires a nuanced understanding of their unique pathologic and biological characteristics and an appreciation of the limitations of the existing evidence. There is a high priority to encourage international collaboration through prospective data collection and randomized trials to provide the required evidence to support treatment guidelines and ultimately improve patient outcomes.

Objective: Patients with platinum-resistant/platinum-refractory high-grade serous ovarian cancer (HGSOC) without a BRCA mutation have poor prognosis and limited treatment options. We report efficacy and biomarker data from EPIK-O, which investigated alpelisib + olaparib versus single-agent chemotherapy in these patients. Methods: EPIK-O was an open-label, phase III trial that randomly assigned patients with platinum-resistant/platinum-refractory HGSOC with no germline or known somatic BRCA mutation 1:1 to alpelisib 200 mg once daily + olaparib 200 mg twice daily or treatment of physician's choice (TPC; paclitaxel 80 mg/m2 once weekly or pegylated liposomal doxorubicin 40-50 mg/m2 once every 28 days). Patients had 1-3 previous systemic therapies. Previous bevacizumab was required (unless contraindicated); previous poly(adenosine diphosphate-ribose) polymerase inhibitors were allowed. Primary end point was progression-free survival (PFS) per RECIST 1.1 (blinded independent review committee [BIRC]). Secondary efficacy end points included overall response rate (ORR; per BIRC), duration of response (per BIRC), and overall survival (OS; key secondary end point). Results: A total of 358 patients (alpelisib + olaparib [n = 180], TPC [n = 178]) were included. The median follow-up time was 9.3 months. At data cutoff (April 21, 2023), 33 (18.3%) and 30 (16.9%) patients remained on treatment with alpelisib + olaparib and TPC, respectively. The median PFS (BIRC) was 3.6 versus 3.9 months (hazard ratio [HR], 1.14 [95% CI, 0.88 to 1.48]; one-sided P = .84) for alpelisib + olaparib versus TPC. The ORR was 15.6% (95% CI, 10.6% to 21.7%) versus 13.5% (95% CI, 8.8% to 19.4%). The median OS was 10.0 versus 10.6 months (HR, 1.22; 95% CI, 0.87 to 1.71). The safety profile of alpelisib + olaparib was consistent with that observed for the individual agents. Conclusions: The primary objective, PFS improvement, was not met in EPIK-O. No new or unexpected adverse events were observed. Biomarker analyses provided new insights for responders to alpelisib + olaparib.

Background: In the VELIA trial, the addition of veliparib to standard first-line platinum-based chemotherapy and continued as maintenance resulted in significantly longer median progression-free survival (PFS) compared with carboplatin plus paclitaxel induction therapy alone (23.5 vs 17.3 months; p < 0.001) in patients with ovarian cancer. We now report final overall survival (OS) and updated safety and disease-related symptoms (DRS) from patient-reported outcomes of the trial. Methods: This randomized, placebo-controlled, double-blind, multicenter, phase 3 study enrolled adult women with an initial diagnosis of stage III/IV high-grade serous ovarian cancer undergoing primary or interval cytoreductive surgery. Patients were randomized 1:1:1 to chemotherapy plus veliparib followed by veliparib maintenance (veliparib-throughout), chemotherapy plus veliparib followed by placebo maintenance (veliparib-combination-only), or chemotherapy plus placebo followed by placebo maintenance (placebo-throughout). PFS was the primary endpoint; OS and DRS were secondary endpoints. Results: In the intention-to-treat population (N = 1140), median OS was 59.2 months (95 % confidence interval: 52.1, 68.2) for the veliparib-throughout group, 58.0 (50.6, 64.1) months for veliparib-combination-only, and 57.8 (52.3, 63.8) months for placebo-throughout. OS outcomes were not significantly different between arms overall or in the BRCA-deficient and homologous recombination-deficient cohorts. No new safety signals were identified during the longer follow-up period and DRS analyses indicated there was no significant additional symptom-related burden overall when veliparib was added to chemotherapy or used for maintenance. Conclusions: No OS or DRS benefit of addition of veliparib to platinum-based chemotherapy and continued as maintenance therapy was detected in this study, despite an observed benefit over chemotherapy alone in PFS.

The current methods to capture and report adverse events (AEs) in clinical trials were developed in the era of cytotoxic chemotherapy and typically focused on higher grade AEs which may lead to severe harms. However, current cancer therapies including targeted agents, checkpoint inhibitors, and antibody drug conjugates are commonly administered for a prolonged duration and result in a cumulative symptom burden which may be inadequately reflected by the conventional approach to capture and reporting of AEs. The limitations include underestimating the chronic AE burden associated with extended exposure, particularly for low to moderate grade symptomatic AEs, and reporting methods that make comparison of similar treatments challenging. Furthermore, the specific AEs that may impact on treatment adherence and lead to dose modifications with oral self-administered therapy are not typically reported. To address these limitations, we recommend: (1) a standardized approach to collection and reporting of patient reported AE data for symptomatic AEs, and reporting methods that incorporate information on the longitudinal characteristics of AEs including duration and trajectory; (2) accurately capturing adherence to oral agents; (3) transparent reporting of the AEs that result in dose reduction and treatment discontinuation in trials; (4) adoption of universal structured AE capture and reporting to allow meaningful comparison of the tolerability profile of therapies. As treatment options increase, optimizing capture and reporting of AEs to include lower grade yet troublesome AEs is essential to provide meaningful information on treatment tolerability to inform both clinicians and patients.

Objective: The optimal treatment of recurrent ovarian clear cell carcinoma (rOCCC) remains unknown. This is the first randomized trial to compare durvalumab with chemotherapy in rOCCC. Methods: MOCCA is a randomized, phase 2 trial conducted in Singapore, Korea and Australia. Eligible patients had rOCCC with recurrence after platinum-based chemotherapy, ECOG performance status ≤2 and no prior immune checkpoint blockade. Patients were randomly assigned (2:1) to durvalumab (1500mg every 4 weeks) or chemotherapy. Patients progressing on chemotherapy were allowed to crossover to durvalumab. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), objective response rates (ORR), and safety. Results: 48 eligible women were assigned to durvalumab (N= 31) or chemotherapy (N= 17). Median PFS was 7.6 (95% CI 7.0-16.0) and 14.0 (95% CI 7.0-32.9) weeks with durvalumab or chemotherapy, (HR 1.6, 95% CI 0.8-3.0; P= 0.92). Median OS was 37.9 (95% CI 21.7-143.0) and 40.6 (95% CI 25.0-not reached) weeks, respectively (HR 1.5, 95% CI 0.7-3.3; P= 0.85). The difference in ORR between groups was not statistically significant (durvalumab 9.7% vs PCC 18.8%; difference -9.1%, 95% CI -31.3%-12.9%; P= 0.83). Fewer all-grade (35.5% vs 68.8%) and high-grade (9.7% vs 31.3%) treatment-related adverse events were observed for durvalumab. PD-L1 CPS+ was observed in 28.9% (CPS≥1%) and 10.5% (CPS≥10%) of patients. PIK3CA mutations were associated with time to progression on durvalumab ³12 weeks (RR(-mutated vs -wildtype) 2.83, 95% CI 1.16 to 14.17). Conclusions: Durvalumab was well-tolerated, but did not improve efficacy outcomes compared with chemotherapy in rOCCC.

A Phase 1b, Open-Label, Dose-escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activities of a RAF Dimer Inhibitor BGB-283 in Combination With MEK Inhibitor PD-0325901 in Patients With Advanced or Refractory Solid Tumors

A Retrospective/Prospective Analysis of Characterization of the Long-Term Responders on Olaparib in Solid Tumours

A Phase 2 Study of Prexasertib in Platinum-Resistant or Refractory Recurrent Ovarian Cancer

A Phase 1/1b, Open Label, Multiple Dose, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activity of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Combination With the PARP Inhibitor BGB-290 in Subjects With Advanced Solid Tumors

A Phase II, Signal-Seeking Trial of the Clinical Benefit Rate Associated With Pamiparib in Subjects With Germline or Somatic BRCA1/2 High Grade Serous Ovarian Cancer or Carcinosarcoma Who Have Progressed on P-gp Substrate Chemotherapy or PARPi With the Presence of an ABCB1 Fusion and the Absence of a BRCA1/2 Reversion