Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma

Abstract

<div class="section"> <a class="named-anchor" id="ab-coi190029-1"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e707">Question</h5> <p id="d1948539e709">What is the clinical activity and safety of combination therapy of niraparib plus pembrolizumab in patients with platinum-based chemotherapy–resistant ovarian carcinoma or those not eligible for retreatment with a platinum-based chemotherapy? </p> </div><div class="section"> <a class="named-anchor" id="ab-coi190029-2"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e712">Findings</h5> <p id="d1948539e714">Sixty-two patients with ovarian carcinoma were enrolled in this open-label, single-arm phases 1 and 2 study. Among the 60 evaluable patients, 3 had complete responses, 8 had partial responses, and 28 had stable disease. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi190029-3"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e717">Meaning</h5> <p id="d1948539e719">Combination niraparib plus pembrolizumab therapy showed promising antitumor activity in patients with ovarian carcinoma, warranting further investigation. </p> </div><p class="first" id="d1948539e722">This open-label, single-arm, phases 1 and 2 study evaluates the poly(adenosine diphosphate–ribose) polymerase inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. </p><div class="section"> <a class="named-anchor" id="ab-coi190029-4"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e726">Importance</h5> <p id="d1948539e728">Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi190029-5"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e731">Objective</h5> <p id="d1948539e733">To evaluate the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi190029-6"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e736">Design, Setting, and Participants</h5> <p id="d1948539e738">The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of <i>BRCA</i> mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi190029-7"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e744">Interventions</h5> <p id="d1948539e746">The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi190029-8"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e749">Main Outcomes and Measures</h5> <p id="d1948539e751">The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi190029-9"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e754">Results</h5> <p id="d1948539e756">Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor <i>BRCA</i> or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi190029-10"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e762">Conclusions and Relevance</h5> <p id="d1948539e764">Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor <i>BRCA</i> mutations or non-HRD cancers were higher than expected with either agent as monotherapy. </p> </div><div class="section"> <a class="named-anchor" id="ab-coi190029-11"> <!-- named anchor --> </a> <h5 class="section-title" id="d1948539e770">Trial Registration</h5> <p id="d1948539e772">ClinicalTrials.gov identifier: <a data-untrusted="" href="https://clinicaltrials.gov/ct2/show/NCT02657889" id="d1948539e774" target="xrefwindow">NCT02657889</a> </p> </div>