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 .

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

“…The most promising strategies for mCRPC treatment combining of two different checkpoint inhibitors or combining one checkpoint inhibitor with enzalutamide, an anti-androgen approved for use in mCRPC [124][125][126]. Recent studies investigating the combination of anti-PD-1 and anti-CTLA4 had promising results in phase I/II and III [127][128][129] with the autologous cellular immunotherapy sipuleucel-T [130]. This treatment consists of autologous peripheral blood mononuclear cells, including antigen-presenting cells, which are previously activated with a recombinant fusion protein that is a prostate antigen fused to granulocyte-macrophage colony-stimulating factor, an immune-cell activator [131,132].…”

Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition

“…The authors, therefore, concluded that these data provided rationale to evaluate combined PARP and immune checkpoint inhibition in BRCA / PALB2 -mutated PDAC patients [ 124 ]. This approach is now showing early promise in ovarian [ 125 ], prostate [ 126 ] and lung cancers [ 127 ]. As mentioned, this approach is now under evaluation in PDAC, including a phase 2 trial evaluating the combination of Pembrolizumab and Olaparib [ 128 ], though this trial and the many similar ongoing studies have yet to post results.…”

Nivolumab plus rucaparib for metastatic castration-resistant prostate cancer: results from the phase 2 CheckMate 9KD trial

“…One such strategy, investigated in several clinical trials, involves combining immune checkpoint inhibitors with other anticancer treatments that have the potential to stimulate an increasingly immune-responsive prostate cancer microenvironment, testing the hypothesis that the immunotherapeutic effects will be augmented and outcomes improved. [4][5][6][7] This combination approach is necessary because treatment with single-agent immune checkpoint inhibitors targeting the anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway does not appear to elicit clinically impactful antitumor responses in unselected mCRPC populations. [8][9][10][11] Although pivotal trials of ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor) monotherapy originally failed to show improvements in overall survival (OS) versus placebo for unselected patients with mCRPC, 12 13 an excess of long-term survivors versus placebo has since been reported in this clinical setting.…”