Prostate cancer ranks as the second most common cause of cancer-related deaths among men in the United States. Aggressive forms of this cancer are linked to mutations in homologous recombination repair (HRRm) genes. The FDA has approved poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib, rucaparib, niraparib, and talazoparib for treating patients with metastatic castration-resistant prostate cancer (mCRPC) associated with HRRm.
Although previous studies have demonstrated that PARP inhibition provides the most significant benefits to patients with HRRm, current data suggest that the responses in HRR genes other than BRCA1/2 and ATM appear to be less effective.
In this retrospective study, the electronic health record was utilized to identify adult patients who were diagnosed with prostate cancer and received treatment at Avera Cancer Institute between January 1, 2018, and December 31, 2022.
These patients underwent somatic and/or germline genetic testing, and the results were reviewed for the presence of pathogenic HRRm genes, including BRCA1, BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C.
Additionally, the patients’ treatment histories were examined to identify the use of PARP inhibition. Information considering the PARP inhibitor received, the duration of treatment, and the biochemical response regarding a decline in prostate-specific antigen levels during therapy was collected.
This analysis included 191 patients. Of these patients, 46% had germline-only testing, 16% had somatic-only testing, and 38% had both germline and somatic testing. A total of 45 patients had HRRm genes, of which 22 were somatic and 33 were germline.
The average patient age at the time of testing was 70 years, and in patients who received PARP inhibitor therapy, the average age at testing was 73 years. Thirteen patients in this cohort received treatment with a PARP inhibitor. Twelve of these patients received treatment with olaparib monotherapy, and 1 patient received olaparib in combination with abiraterone.
The average progression-free survival (PFS) was 26 months, and the median PFS was 11 months. Four patients were biochemical nonresponders, with an average PFS of 8 months, compared with 33 months for the 9 biochemical responders (P=.04). In nonresponders, the detected gene alterations 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).
The patients diagnosed with HRRm and subsequently treated with a PARP inhibitor exhibited comparable responses to previously reported data. Specifically, the group with BRCA2 mutations displayed the most favorable response, followed by tumors with PALB2 mutations. The overall number of patients with HRRm who received PARP inhibitor treatment was lower than anticipated, which necessitates further investigation. The introduction of new FDA-approved PARP inhibitors in combination with next-generation hormonal agents in the first-line mCRPC setting is expected to enhance the utilization of PARP inhibitors.
Gathering additional outcomes data for individual HRR genes is imperative to enhance patient selection and outcomes and minimize unnecessary toxicity associated with PARP inhibitor therapy.
Alstyne TV, Corsini C, Owen P, et al. Utilization of genetic and genomic data and correlation to outcomes of treatment with PARP inhibitors in advanced or metastatic castrate-resistant prostate cancer. Chicago, IL, & online: presented at 2024 ASCO Annual Meeting; June 1, 2024: abstract e17034.
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