ROCSAN trial (GINECO-EN203b/ENGOT-EN8): A multicentric randomized phase II/III evaluating dostarlimab in combination with niraparib versus niraparib alone compared to chemotherapy in the treatment of endometrial/ovarian carcinosarcoma after at least one line of platinum based chemotherapy.

Abstract

TPS5604 Background: Gynecological carcinosarcomas (CS) are rare and highly aggressive tumors with a 5-year overall survival (OS) < 10%. After initial treatment majority of patients (pts) relapse and receive diverse chemotherapies (CT) producing modest benefits. The median PFS in relapse after platinum based CT is less than 4 months and median OS less than 1 year. New innovative strategies are urgently needed. Since CS showed high DNA damage response activity and potentially a high tumor mutation load resulting in neo-antigens, a synergy between PARPi and anti-PD1 is expected. Methods: ROCSAN is a multicentric, randomized, open-label, integrated Phase II/III study. In the Phase II, 63 pts with recurrent or progressing endometrial or ovarian CS after at least a first line of platinum-based CT will be randomized (2:2:1) to receive either niraparib in monotherapy, niraparib in combination with dostarlimab or standard CT (paclitaxel, doxorubicine, gemcitabine, topotecan). Stratification factors include the number of previous CT lines (1 vs 2-3), FIGO stage at diagnosis (I-II vs III-IV), CS localisation (ovarian vs endometrial), and performance status (0-1 vs 2). The primary objective of the Phase II is to select the best experimental strategy between niraparib and dostarlimab/niraparib combination based on Response Rate at 4 months (RR-4M by RECIST1.1). A single stage design with a 10% unacceptable RR-4M and a 30% targeted RR-4M was used to determine Phase II sample size, assuming a 10% one sided alpha for each comparison and more than 90% power. A pick-the-winner selection design could be used in case of promising efficacy in each experimental arm. At the interim analysis, an Independent Data Monitoring Committee will make recommendation for the selection of the optimal experimental arm. The Steering committee could then support to continue enrolment for the international Phase III which is calibrated to detect an improvement in median OS from 7 months (Standard CT) to 11.7 months (best experimental arm). Assuming a 5% alpha level and 80% power, 133 additional pts could be randomized (2:1). Secondary endpoints include safety, PFS, PFS2, TTST, ORR, duration of response, patient report outcomes (assessed via EORTC QLQ-C30 OV28, HADS, PRO-CTCAE). A translational program supported by European Community is associated to the clinical study to identify predictive biomarkers of response/resistance to study treatments, to correlate with immune environment, a special focus on genetic instability and the EMT process will be included. Trial is currently recruiting only in France for the phase II part, the first pt was randomized in July 2020. Clinical trial information: NCT 03651206.

Therapeutic Challenges in Patients with Gynecologic Carcinosarcomas: Analysis of a Multicenter National Cohort Study from the French Prospective TMRG Network

“…Currently, the ROCSAN trial (NCT03651206) is dedicated to recurrent carcinosarcomas, testing other therapeutic avenues in this patient population with limited treatment options. This phase II/III trial provides the opportunity to assess the combination of PD-1 and PARP inhibition [ 59 ]. Although data have not yet emerged from this study, this combination is a promising treatment regimen.…”

Management and Prognosis of Patients with Recurrent or Persistent/Progressive Uterine Carcinosarcoma

“…Hunt et al presented a small retrospective series with pembrolizumab and lenvatinib in seven patients of advanced or recurrent UCS as ≥ third-line, which observed no partial or complete response [ 40 ], while it was unknown if used earlier at first relapse. A ROCSAN trial with an anti-PD1 (dostarlimab) and a PARPi (niraparib) is now recruiting [ 41 ]. Of the four cases in our series that used pembrolizumab, two patients ( Table 6 , Patient 2, 6) with durable anti-tumor effects were observed, with 21.4 and 13.1 months SAR.…”

Latest advances in immuno-oncology for endometrial cancer: single-agent and combination regimens

“…For those patients with MMRd, the KEYNOTE-C93/GOG-3064/ENGOT-en15 will also investigate single-agent pembrolizumab vs. carboplatin/paclixatel [47]. The DOMENICA trial is investigating a similar population with dostarlimab [48]. Dual ICI in the form of nivolumab combined with ipilimumab is also under investigation in the NRG-GY025 randomized phase II trial [49].…”