Utilization of genetic and genomic data and correlation to outcomes of treatment with PARP inhibitors in advanced or metastatic castrate-resistant prostate cancer.
Authors: Van Alstyne Ted , Corsini Connor , Owen Parker , Elsey Rachel , Hattum Crystal , Meissner Tobias , Solomon Benjamin Maurice , Williams Casey B. 
Published: July 2024

e17034

Background: Prostate cancer is the second-leading cause of cancer death in men in the United States, with aggressive forms associated with mutations in homologous recombination repair (HRRm) genes. PARP inhibitors (PARPi) (olaparib, rucaparib, niraparib, and talazoparib) are FDA approved for treatment of HRRm metastatic castration-resistant prostate cancer (mCRPC). Previous data have shown PARPi has the greatest benefit in patients with HRRm, but the responses in HRR genes other than BRCA1/2 and ATM are less robust based on available data. Methods: This retrospective study utilized the electronic health record to identify adult patients diagnosed with prostate cancer and treated at Avera Cancer Institute from 1/1/2018 to 12/31/2022 who received somatic (tumor and/or ctDNA) and/or germline genetic testing. Testing results were reviewed for pathogenic HRRm (BRCA1, BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) and treatment histories were reviewed to identify PARPi use. Data about PARPi received, duration, and biochemical response (decline in PSA during therapy) were collected. Results: 191 patients were included in the final analysis. Of these, 88 (46%) patients had germline only testing, 31 (16%) had somatic only testing, and 72 (38%) had both germline and somatic testing completed. 45 patients had HRRm of which 22 were somatic and 33 were germline. The average patient age at time of testing was 70 years. Thirteen of the patients in this cohort received treatment with a PARPi . Twelve of these patients received treatment with olaparib monotherapy, and one patient received olaparib in combination with abiraterone. Average progression free survival was 26 months (range 5-92 months) and the median PFS was 11 months. Four patients were biochemical non-responders, with an average PFS of 8 months, compared to 33 months for the 9 biochemical responders (p=0.04). Gene alterations present in non-responders included germline BRCA1 (n=1), germline CHEK2 (n=2), and somatic ATM (n=1). Germline alterations present in responders included BRCA2 (n=7) and PALB2 (n=2). In patients who received PARPi therapy, the average age of testing was 73 years. Conclusions: The patients found to have HRRm that were treated with a PARPi showed similar responses to previously described data in that the BRCA2 mutated group showed best response, followed by PALB2 mutated tumors. The overall proportion of patients with HRRm that were ultimately treated with PARPi was smaller than expected warranting further investigation. New FDA approvals of PARPi combined with next generation hormonal agents in the first line mCRPC setting are expected to increase utilization of PARPi. Additional outcomes data for individual HRR genes are needed to improve patient selection, outcomes, and reduce unnecessary toxicity due to PARPi therapy.