Abstract B009: A panel-based mutational signature of homologous recombination deficiency associates with response to PARP inhibition in metastatic castration-resistant prostate cancer
Authors: Boiarsky Daniel , Tewari Alok , Gulhan Doga , Bakouny Ziad , Ananda Guruprasad , Savignano Hunter , Lakshminarayana Gitanjali , Choueiri Toni K , Taplin Mary-Ellen , Berchuk Jacob E 
Published: December 2023

Background. The PARP inhibitor (PARPi) Olaparib is FDA-approved for treatment of metastatic castration-resistant prostate cancer (mCRPC) harboring a deleterious alteration in specific homologous recombination (HR) genes based on results of the PROfound trial. Qualifying HR gene alterations include BRCA1, BRCA2, ATM (Cohort A), and BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51C, RAD51D (Cohort B). However, there is heterogeneity in the degree to which different HR genes associate with response to PARPi. Better clinical biomarkers are needed to accurately identify patients likely to benefit from PARPi.

Methods. Patients with prostate adenocarcinoma who underwent panel sequencing (OncoPanel V3) at the Dana-Farber Cancer Institute were identified. Patients were classified on the presence of pathogenic alterations in Cohort A or B genes from PROfound. The computational tool SigMA was applied to detect a mutational signature of HR deficiency (sHRD). Clinical outcomes in patients treated with Olaparib were collected. Differences between groups were compared using Fisher's exact test and survival analyses were performed using the Kaplan-Meier and Cox Proportional Hazards methods. P&lt;0.05 was considered significant.

Results. 492 patients were identified, of which 33% were sHRD. A significantly higher proportion of patients were sHRD in those with Cohort A alterations vs no HR alteration (47% vs 30%, P = 0.0020); however, there was no difference in the rates of sHRD between patients with Cohort B alterations vs no HR alterations. When stratifying patients by individual HR alterations, only those with BRCA1/2 two-copy loss (2CL) were significantly more likely to be sHRD compared to patients with no HR alteration (79% vs 30%; P = 9.1 x 10-8).  31 patients with mCRPC were treated with Olaparib, of which 12 (39%) were sHRD. Of those 12, 8 had BRCA2 2CL, 1 had an ATM 2CL and three had no HR alteration. There was no difference in the rate of PSA50 responses between patients with vs without Cohort A+B alterations (37% vs 8.3%; P = 0.11), while patients with vs without sHRD were significantly more likely to achieve PSA50 (67% vs 0%; P = 6.3 x 10-5). Patients with Cohort A+B alterations (HR = 0.31, P = 0.0046) and sHRD (HR = 0.088; P = 1.9 x 10-5) exhibited significantly improved radiographic progression-free survival (rPFS) to Olaparib compared to those lacking the biomarker. However, on multivariate analysis, including clinical variables associated with improved rPFS to Olaparib, the presence of BRCA2 2CL (the alteration most strongly associated with PARPi response), and sHRD, sHRD was the only variable independently associated with improved rPFS to Olaparib (HR = 0.15, P = 0.012). The potential value of sHRD was exemplified by an sHRD patient without a HR alteration who exhibited a 64% decline in PSA from baseline and an rPFS of 11 months on Olaparib.

Conclusion. SigMA-predicted HRD outperformed the current FDA-approved biomarker (deleterious alterations in one of 14 HR genes) for identifying patients with mCRPC likely to benefit from Olaparib.

Citation Format: Daniel Boiarsky, Alok Tewari, Doga Gulhan, Ziad Bakouny, Guruprasad Ananda, Hunter Savignano, Gitanjali Lakshminarayana, Toni K Choueiri, Mary-Ellen Taplin, Jacob E Berchuk. A panel-based mutational signature of homologous recombination deficiency associates with response to PARP inhibition in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B009.