Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations

Abstract

Background: Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations.

Methods: Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations.

Results: Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5-16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7-72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8-18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response.

Conclusions: Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities.

Trial registration: ClinicalTrials.gov identifier: NCT02484404 .

Keywords: Abiraterone; Anti-PD-L1; Durvalumab; Enzalutamide; Immunotherapy; Olaparib; PARP inhibitor; mCRPC.

Fig. 1

PSA Response. a Waterfall plot demonstrating maximum decline in PSA for each patient. Bar colors represent radiographic response by RECIST criteria: green, partial response; blue, stable disease; red, progressive disease; gray, not assessable (bone-only disease). b Spider plot of PSA responses over time

Fig. 2

Progression-Free Survival. At median potential follow-up of 9.7 months, radiographic PFS for all patients with durvalumab plus olaparib (n = 17) is 16.1 months

Fig. 3

Early Markers of Response Are Associated with Progression-Free Survival. a Kaplan-Meier curve showing that patients with <= median percentage of MDSCs at baseline had prolonged PFS. b Change in CTC numeration from C1D1 to C3D1. c Decrease or no change in in CTC count from C1D1 to C1D15 correlated with increased PFS. d Kaplan-Meier curve demonstrating that increased DC maturity (as demonstrated by CD83 expression on CD141⁺ mDCs from baseline to C1D15) was associated with prolonged PFS. e Kaplan-Meier curve demonstrating that patients with > median percentage of K67⁺PD⁻1⁺CD8⁺ T cells among total CD8⁺ T cells at C1D15 had prolonged PFS. f Kaplan-Meier curve demonstrating that patients with > median percentage of K67⁺PD⁻ 1⁺CD4⁺ T cells among total CD4⁺ T cells at C3D1 had prolonged PFS

Fig. 4

Genomic Alterations. Presence or absence of alterations in DDR and other significant genes. Genomic data are from OncoVar sequencing, a capture-based sequencing panel of 500 cancer-associated genes. Copy number calls are based on read depth and minor allele frequency in the OncoVar sequencing results. All patients had germline sequencing performed. As indicated, 3 patients had insufficient tumor tissue on biopsy and no archival tissue available