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Maintenance; Olaparib; Ovarian cancer Manteniment; Olaparib; Càncer d'ovaris Mantenimiento; Olaparib; Cáncer de ovarios Objective The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. Methods In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18 months after the last patient received their first dose. Results Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2 months (95% confidence interval [CI], 7.6–10.9) in the overall population. At 12 and 18 months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3 months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. Conclusion Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals. This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Background While early stage endometrial cancer (EC) is associated with a favorable prognosis, prognosis for advanced or recurrent EC is poor. Paclitaxel and carboplatin chemotherapy (CT) is often used as first-line treatment for these patients; however, there exists an imperative need for more effective and tolerable therapies. In KEYNOTE-146, combination therapy with the PD-1 inhibitor pembrolizumab (pembro) and the tyrosine kinase inhibitor lenvatinib resulted in an ORR of 39% in patients with EC (Makker et al. ASCO 2018). Based on these promising data, the ENGOT-EN9/LEAP-001 study was initiated to assess this combination therapy in women with recurrent or advanced EC. Trial design The ENGOT-EN9/LEAP-001 study (NCT03884101) is a phase 3, randomized, open-label, active-controlled trial comparing combination therapy with pembro and lenvatinib to paclitaxel and carboplatin CT in patients with newly diagnosed stage III-IV or recurrent EC (NCT03884101). Approximately 720 patients not previously treated with systemic chemotherapy (except as part of a chemoradiation regimen), antiangiogenic agents, PD-1 or PD-L1 inhibitors, or other T-cell receptor–targeted agents will be randomized 1:1 to pembro (200 mg Q3W) plus lenvatinib (20 mg daily) or paclitaxel and carboplatin CT (pac 175 mg/m2 plus carb AUC 6 Q3W). Patients will first be stratified by proficient vs deficient mismatch repair status (pMMR vs dMMR), and pMMR patients will be further stratified by ECOG performance status (0 vs 1), measurable disease (yes vs no), and prior chemoradiation (yes vs no). Treatment will continue until disease progression, initiation of new anticancer treatment, unacceptable adverse events, or withdrawal of consent for up to 35 cycles for pembro or 7 cycles of paclitaxel and carboplatin CT. Primary endpoints are PFS per RECIST v1.1, assessed by blinded independent central review, and OS. Secondary endpoints are ORR, health-related quality of life, safety and tolerability, and pharmacokinetics of lenvatinib. Exploratory endpoints include duration of response, disease control rate, and clinical benefit rate. Enrollment is ongoing. Clinical trial identification NCT03884101; 21, 2019. Editorial acknowledgement Nathan Rodeberg, PhD, and Diane Neer, ELS, of MedThink SciCom, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA, are responsible for the governance, coordination and running of the study. Funding Funding for this study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA. Disclosure C. Vulsteke: Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self): Janssen; Honoraria (self): Novartis; Honoraria (self): Leo-Pharma; Honoraria (self): Merck MSD; Honoraria (self): AstraZeneca; Honoraria (self): Astellas. V. Makker: Advisory / Consultancy: Eisai; Advisory / Consultancy: Merck; Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy: ArQule; Research grant / Funding (self): Karyopharm; Research grant / Funding (self): AstraZeneca. I.A. McNeish: Honoraria (self): Clovis Oncology; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Takeda; Honoraria (self): Tesaro. L. Dutta: Full / Part-time employment: Eisai. C. Xu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. S.M. Keefe: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. J. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. S. Pignata: Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Honoraria (self): Clovis Oncology; Honoraria (self): Tesaro; Honoraria (self): Inctre. All other authors have declared no conflicts of interest.