Randomized phase II trial of olaparib and pembrolizumab vs olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2) mutations: SWOG S2001.

4012 Background: Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. The POLAR trial demonstrated promising results combining pembrolizumab with olaparib as maintenance therapy in patients (pts) with homologous recombination deficiency (HRD) mutations. S2001 is a randomized phase II trial evaluating the addition of pembrolizumab to olaparib as maintenance therapy in patients with gBRCA1/2. Methods: Eligible pts had mPDA with gBRCA1/2 mutations and had received a minimum of 4 months of platinum-based chemotherapy without progression. Pts were randomized 1:1 to olaparib 300 mg twice per day plus pembrolizumab 200 mg every 3 weeks or olaparib alone. The primary endpoint was progression-free survival (PFS) with a target hazard ratio (HR) of 0.6 (median PFS 7.0 vs 11.7 months) with 1-sided alpha=0.1 and 80% power. Secondary outcomes were safety and tolerability, overall survival (OS), overall response rate (ORR), and disease control rate (DCR). The accrual goal was 88 pts to have 78 eligible for analysis. Differences in PFS by treatment arm were assessed via stratified log-rank test, with first line platinum-based chemotherapy, Zubrod PS, and disease status after first line treatment as stratification factors. Tissue and blood samples for correlative studies were banked. Results: The study enrolled 73 patients, with 68 eligible, and was closed for futility after a planned interim analysis showed that PFS was not improved in the pembrolizumab + olaparib arm (p=0.82), despite higher ORR (p=0.20) (Table). Treatment was well tolerated, with no grade 4-5 treatment-related adverse events and similar toxicity profiles across arms. Autoimmune toxicities on the experimental arm included adrenal insufficiency, hyperthyroidism, and hypothyroidism. Grade 3 adverse events in both arms included neutropenia, anemia, thrombocytopenia, gastrointestinal toxicity and fatigue. Conclusions: S2001 is the first randomized controlled trial evaluating the addition of pembrolizumab to olaparib in pancreas cancer. Despite doubling the ORR and improvement in DCR and PFS in the experimental arm, the high bar of improving PFS to 11.7 months was not met. Activity seen in the experimental arm of S2001 is comparable to the HRD cohort of the POLAR trial which demonstrated ORR 35%, DCR 90% and PFS of 8.2 months. Further follow-up for mature survival outcomes and translational analysis of DNA and RNA are planned. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819 with additional support from by Merck & Co, Inc. Clinical trial information: NCT04548752 . Pembrolizumab + Olaparib (n=34) Olaparib (n=34) Median PFS 8.2 months 6.4 months Median OS 20.0 months 22.1 months ORR 28.1% 14.3% DCR 84.4% 64.3%