Pembrolizumab (pembro) plus olaparib in patients (pts) with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort A efficacy, safety, and biomarker results.

Abstract

5544 Background: Pembro + olaparib has shown antitumor activity and acceptable safety in docetaxel-pretreated pts with mCRPC enrolled in cohort A of the phase I/II KEYNOTE-365 study (NCT02861573). Updated results with new biomarker data are reported. Methods: Pts with docetaxel-pretreated mCRPC who progressed within 6 mo of screening received pembro 200 mg IV Q3W + olaparib 400-mg capsule or 300-mg tablet PO BID. Pts might have received 1 other chemotherapy and ≤2 second-generation androgen-receptor targeted therapies. Primary end points: PSA response rate (decrease ≥50% from baseline, confirmed by a second value ≥3 wks later), ORR per RECIST v1.1, and safety. Key secondary end points: DCR, DOR, rPFS, and OS. Biospecimens (eg, blood, tissue) were collected for biomarker analysis (tissue PD-L1 expression, androgen receptor variant 7 [AR-v7] expression in circulating tumor cells [CTCs], and a T-cell–inflamed gene expression profile [GEP]). ctDNA was analyzed by Guardant Health 360 (GH360) and Omni (GH Omni) assays. FFPE tissue was analyzed by FoundationOne CDx (F1CDx) assay. Results: 84 of 87 enrolled pts were treated; 48/84 (57.1%) had measurable disease. Median (range) time from enrollment to data cutoff was 3.6 mo (0.0-29.2) for all pts and 26.7 mo (21.2-29.2) for 41 pts with ≥27 wks’ follow-up. Confirmed PSA response rate was 9% (95% CI, 3.5-16.8) in 82 pts with a baseline PSA assessment. Median time to PSA progression: 3.8 mo (95% CI, 2.9-4.4). In 24 pts with measurable disease and ≥27 wks’ follow-up, ORR was 8.3% (95% CI, 1.0-27.0; 2 PRs) and DCR ≥6 mo was 20.8% (95% CI, 7.1-42.2). Median (range) DOR was NR (12.0+ to 21.4+ mo); 2 pts had DOR ≥12 mo. In all pts, median rPFS was 4.3 mo (95% CI, 3.4-7.7) and median OS was 14.4 mo (95% CI, 8.1-18.5). Grade ≥3 TRAEs occurred in 29 pts (35%); 2 pts died of TRAEs (1 myocardial infarction, 1 unknown). Overall, 26% had PD-L1+ tumors (combined positive score ≥1). Of 31 pts with CTC data, 12.9% were AR-v7+. No BRCA1/2 mutation was detected by GH360 (n=42). Of 57 pts analyzed by GH Omni, 2 had BRCA2 mutations, 1 had a BRCA1 mutation, 4 had ATM mutations, 1 had a CHEK1 mutation, and 6 had CDK12 mutations. Of 49 pts analyzed by F1CDx, 4 had BRCA mutations; 1 pt had a copy number loss mutation not detected by ctDNA analysis. GEP was not associated with ORR or PSA response. Conclusions: Pembro + olaparib continued to show activity and acceptable safety in pts with docetaxel-pretreated mCRPC. A phase III study of this combination is ongoing (KEYLYNK-010, NCT03834519). Clinical trial information: NCT02861573 .