BACKGROUND: PARP inhibitors (PARPi’s) were recently approved for the treatment of metastatic prostate cancer among patients harboring mutations in an array of genes responsible for DNA repair. We sought to identify whether a subset of these genes correlates with response to treatment more frequently than others. Consequently, an evaluation of the specific DNA repair genotypes associated with durable clinical benefit (DCB) using real-world patient data was undertaken.
METHODS: The U.S. Department of Veterans Affairs (VA) National Precision Oncology Program’s (NPOP) database and Corporate Data Warehouse (CDW) were reviewed to select patients who (1) carried a diagnosis of prostate cancer, (2) successfully underwent tumor DNA sequencing through NPOP, (3) were prescribed olaparib, rucaparib, nirapib, and/or talazaporib for their prostate cancer between July 2016 and February 2020, and (4) and achieved DCB, defined as no progression in prostate-specific antigen (PSA) for at least 6 months following PARPi initiation without concurrent systemic or non-systemic therapies other than androgen-deprivation. The DNA repair gene variants and orders placed for NPOP consultative support were reviewed.
RESULTS: Of the 44 prostate cancer patients treated with a PARPi, 6 (13.6%) had tumor DNA sequencing through NPOP and had achieved DCB. Five patients were treated with olaparib and 1 with rucaparib. The median PSA progression-free survival was 8.9 (interquartile range = 8.5 – 11.2) months among these selected patients. Regarding gene variants, 5 patients had 7 BRCA2 mutations, including 4 frameshift, 1 nonsense, 1 single nucleotide variant, and 1 splice site. One patient had frameshift and missense ATM mutations. Referrals to the NPOP consult service were ordered for 2 out of the 5 patients with BRCA2 mutations achieving DCB.
CONCLUSIONS: Within the VA’s NPOP, the presence of BRCA2 gene variants was the most common finding from tumor DNA sequencing among patients with prostate cancer achieving DCB with a PARPi. Further analysis of the genotypes of all patients treated with PARPi in NPOP to assess the differential impact of BRCA2 mutations is needed to confirm the clinical implication of this finding.