Abstract P3-10-19: Phase II Trial of Pembrolizumab in Combination with Olaparib in Advanced Breast Cancer with BRCA-mutation or Homologous Recombination Defect (HRD)

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Abstract Background: Tumors with HRD showed similar propensity to be sensitive to poly ADP-ribose polymerase inhibitors (PARPi) inhibitors as BRCA-mutated tumors. The rationale for combining PARP inhibitors with immune checkpoint inhibitors (ICIs) comes from the observation that PARPi induces PD-L1 and triggers robust local and systemic antitumor immunity via STING-dependent pathways, which in turn synergizes with ICIs. This study was designed to test the effectiveness of this combination in breast cancer patients with HRD defects or BRCA mutations. Methods: This is an open-label, single-center, phase 2 study for breast cancer with BRCA-mutated or HRD cancer progressing on prior therapies for metastatic or locally advanced disease with no restriction of receptor status. All commercially available HRD assays are acceptable. Eligible pts received pembrolizumab 200 mg IV every 21 days combined with olaparib 300 mg PO daily. Treatment was continued until documented progression by RECIST 1.1 or unacceptable toxicity. The primary objective was the overall response rate (ORR) of the combination therapy, with secondary objectives being progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Adverse events (AEs) were monitored using CTCAE v.5.0. Results: Twelve pts were included in this preliminary analysis. The median age at study entry was 50 (Range 33-73). Of these, 8 pts(66.7%) were White, including 1 Hispanic; 1 pt was African American, and 1 pt was Asian. Ten pts had hormone receptor-positive HER2-negative disease, and 2 patients had triple-negative disease. The pts had received median 4 lines of treatment (Range 1-10) prior to study entry. Six pts and 2 pts had received prior PARPi and ICI respectively, including 1pt who had received both agents at separate times. Treatment response was not evaluable for 2 patients: 1 withdrew consent after cycle 1, and 1 had disease progression during cycle 1 of treatment. Germline BRCA1 and BRCA2 mutations were found in 3 patients (25.0%) and 4 patients (33.3%), respectively. ORR was 33.3% (3 partial responses and 0 complete responses). Median PFS was 3.7 months, and median OS was 5.7 months. Median DOR was 2.2 months. Currently, one pt has been on treatment for over 8 months, with stable disease after 4 months of partial response. The most common adverse events were nausea (7 patients; 4 pt with grade 1-2, 3 pt with grade 3) and anemia (5 patients, all grade 1-2). Other grade 3 toxicities were muscular-skeletal pain in 1pt, fatigue in 1pt, leukopenia in 1pt and pneumonia in 1pt. There was no grade 4-5 toxicity. Conclusions: The combination of olaparib and pembrolizumab was well tolerated, with ORR of 33.3% in heavily pretreated breast cancer patients, including patients with prior PARPi exposure. This trial is ongoing to finalize the clinical benefits assessment. Clinical trial information: NCT03025035 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA provided pembrolizumab, olaparib, and financial support for the study. Citation Format: Jin Sun Bitar, Monica Mita, Philomena McAndrew, Dorothy Park, Reva Basho, Joey Di Padova, Marie Lauzon, Yuan Yuan. Phase II Trial of Pembrolizumab in Combination with Olaparib in Advanced Breast Cancer with BRCA-mutation or Homologous Recombination Defect (HRD) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-10-19.

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