Trial in progress: Durvalumab and olaparib for the treatment of prostate cancer in men predicted to have a high neoantigen load.

Abstract

TPS5099 Background: Approximately 30% of patients (pts) treated with definitive surgical and/or radiation therapy for localized prostate adenocarcinoma develop biochemical recurrence (BCR). The optimal time to initiate androgen deprivation therapy (ADT) for such patients is controversial and depends on patient and provider preference, absolute PSA value, and PSA doubling time (PSADT), which has been associated with time to metastasis. Because the time from BCR to metastasis can be long in many cases, strategies allowing pts to avoid ADT while extending metastasis-free survival are desirable. Prior studies have shown that a high tumor neoantigen load correlates with response to anti-PD(L)1. We hypothesized that PARP inhibitor-induced genomic instability may sensitize tumors to anti-PD(L)1 through: i) increasing mutational burden and subsequent tumor neoantigen formation, and/or ii) through activation of other immunogenic pathways (e.g. the STING pathway). This trial investigates an ADT-sparing approach for men predicted to have high neoantigen load and who have BCR prostate cancer. Methods: This is a phase 2 clinical trial testing durvalumab (1500 mg IV every 4 weeks) and olaparib (300 mg PO twice a day) (one cycle = 4 weeks) in men with BCR (PSADT≤10 months) whose tumors are predicted to have high neoantigen load based on: biallelic CDK12 mutations (Cohort A), mismatch repair deficiency (MMRd)/high microsatellite instability (MSI-H) (Cohort B), or loss of function mutations in homologous recombination repair (HRR) genes (Cohort C). Cohorts A and B will receive 3 cycles of durvalumab followed by 3 cycles of the combination of durvalumab and olaparib. Given the proven efficacy of olaparib in prostate cancer patient whose tumors posses an HRR gene mutation, Cohort C will receive 6 full cycles of the combination. Ten patients will be enrolled in each cohort (total n = 30) at two collaborating sites. This study was designed to provide preliminary efficacy data across eligible cohorts, with a primary objective of estimating the proportion of pts with an undetectable PSA at 12 months within each cohort. Secondary objectives include safety, proportion of patients with ≥50% decline in PSA from baseline and quality of life measures. Correlative studies will assess blood and tissue molecular biomarkers for association with outcomes. The study is open with two patients enrolled at the time of abstract submission. Clinical trial information: NCT04336943.