1504MO - Phase II trial of Pembrolizumab and OLApaRib (POLAR) maintenance for select patients (pts) with metastatic pancreatic cancer (mPC) with (A) homologous recombination deficiency (HRD), (B) non-core HRD (ncHRD) and (C) exceptional response to platinum

Background

Maintenance olaparib improves progression-free survival (PFS) of gBRCA1/2m (HRD) mPC: 6-month (M) PFS 50% and objective response rate (ORR) 20% (Golan NEJM 2019). We hypothesized that select mPC are more immunogenic and adding PD-1 inhibitor (pembrolizumab) to olaparib may improve survival.

Methods

Phase 2, open-label 3-cohort design for specific genotypes & phenotypes: A) gsBRCA1/2/PALB2m (HRD) & platinum ≥ 4M, B) other HRD-gene mutations (ncHRD) & platinum ≥ 4M, C) no HRD but platinum response ≥ 6M. Eligibility: ECOG 0-1, mPC on 1L/2L platinum. POLAR (Pembrolizumab 200mg IV Q3W+ OLApaRib 300mg BID) until progression or toxicity. Co-primary endpoints for A: 6M-PFS rate & ORR. B/C: exploratory. Positive study: ≥ 70% 6M-PFS (23/33 pts) or ORR ≥ 36% in RECIST-evaluable pts. Median PFS, median overall survival (mOS), 6M-disease control rate (DCR), and comprehensive immunogenomic correlatives were obtained.

Results

As of 4/19/24, N=63 pts enrolled (A: N=33 & B/C: N=15 each). Cohort A: the median follow-up was 10.6M (1.4-37.9). N=19/29 pts with mature 6M follow-up were progression free. 6M-PFS was 64% (95%CI: 49-84) by Kaplan-Meier method. N=6 pts on active POLAR ≥ 1.5 years. Cohort B: 6M-PFS rate of 47%. Efficacy details summarized in the table. N=23 G3-4 treatment-related AEs: 11 anemia (17%), 2 pancreatitis (3%), 2 colitis, 1 pneumonitis, 1 fatigue, 1 hyperglycemia. N=9 G3 AEs in 8 pts: 3 bowel obstruction, 1 hyperbilirubinemia, 1 seizure, 1 neutropenia, 1 diarrhea, 1 acute kidney injury. 33 HRD included 19 gsBRCA2m, 8 gsBRCA1m, 6 gPALB2m. ncHRD: 8 ATM, 3 CHEK2, 2 MUTYH, 1 BLM, 1 FANCC. Baseline biomarkers per cohort are summarized in the table. Table: 1504MO

Conclusions

Significant clinical activity of POLAR maintenance in select mPC. Mature data and correlative science will be presented. Funding: Merck, SPORE (1P50CA257881-01A1), PICI, NIH-K12. NCT04666740.

Clinical trial identification

NCT04666740.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Merck, National lnstitute for Health (NIH)- National Cancer Institute (NCI)- SPORE (1P50CA257881-01A1), Parker Institute for Cancer Immunotherapy, NIH-K12.

Disclosure

W. Park: Financial Interests, Personal, Other, Consultancy: Astellas; Financial Interests, Personal, Advisory Board: Exact Therapeutics; Financial Interests, Personal, Invited Speaker, Continuing Medical Education: American Physician Institute, Integrity; Financial Interests, Institutional, Research Grant: Merck, Break Through Cancer, Parker Institute for Cancer Immunotherapy, The Society of MSK, National Institute of Health - National Cancer Institute; Financial Interests, Institutional, Local PI: Astellas, Miracogen, Amgen, Revolution Medicines. A. Varghese: Financial Interests, Institutional, Local PI, Institutional PI of multi-institution clinical trial: Bristol Myers Squibb, GSK, Lilly Oncology, OBI Pharma, Inc., Silenseed Ltd. K. Yu: Financial Interests, Personal, Speaker, Consultant, Advisor: Ipsen Pharmaceuticals. D. Kelsen: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, Bristol Myers Squibb, AbbVie, Guardant, Incyte; Financial Interests, Personal and Institutional, Research Funding: Thompson Family Foundation, Applebaum Foundation. N. Riaz: Financial Interests, Institutional, Research Funding: Repare Therapeutics, Bristol Myers Squibb, Pfizer. M. Berger: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Eli Lilly, Paige AI. V. Balachandran: Financial Interests, Personal and Institutional, Research Funding, Professional Services and Activities: Genentech. D. Peer: Financial Interests, Personal, Other, Equity, professional service, activities: Insitro, Inc. C. Iacobuzio-Donahue: Financial Interests, Personal and Institutional, Research Funding: Bristol Myers Squibb. E.M. O'Reilly: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, BioNTech, Merck, AstraZeneca, Novartis, FibroGen, Astellas, Tempus, Merus, BMS, Berry Genomics, Exelixis, Incyte, Neogene, Sevier, Thetis, Vector, Yiviva; Financial Interests, Personal, Advisory Board, +Spouse: Ipsen; Financial Interests, Personal, Advisory Board, Spouse: Genentech/Roche, Eisai; Financial Interests, Personal, Advisory Board, + spouse: Autem; Financial Interests, Institutional, Local PI: Genentech/Roche, Arcus, Elicio; Financial Interests, Personal and Institutional, Coordinating PI: BioNTech; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Pertzye; Financial Interests, Institutional, Research Grant: Parker Institute; Non-Financial Interests, Other, Scientific and Medical Advisory Board: Pancreas Cancer Action Network; Non-Financial Interests, Member of Board of Directors: National Pancreas Foundation; Other, Editor: American Society of Clinical Oncology, American Association of Cancer Research (AACR). All other authors have declared no conflicts of interest.