Introduction:

Germline pathogenic variants are present in up to 12% of metastatic prostate cancer (mPCa) cases. Besides the benefit for genetic counseling in families, the primary benefit of testing in this setting is the treatment implications for the patient. To this end, two PARP inhibitors, rucaparib and olaparib, were recently FDA-approved for the treatment of BRCA or homologous recombination repair (HRR)-mutated mPCa. Despite NCCN guidance to test all mPCa patients, there are still barriers to implementing this in practice, including lack of effective workflows and insurance concerns. A sponsored no-charge testing program was initiated that provides a simplified framework to support testing and remove the need for insurance coverage, thereby expanding access to testing to more patients who could benefit from precision therapy.

Methods:

We analyzed de-identified data from July 2019-June 2020 for 1049 men with reported mPC, a subset of the larger cohort of men tested through the program  who had been selected with the sole criterion that their stage of disease was ≥T2. Positive results were categorized as: pathogenic (P), likely pathogenic (LP), or increased risk allele (IRA) (HOXB13 G84E and APC I1307K). 

Results:

Overall, 128 (12.2%) men were positive, including 127 P/LP variants in 34 genes and 12 IRAs. The majority of men with P/LP results (n=74; 63%) had variants in HRR genes conferring precision therapy eligibility, and an additional 29 men had variants relevant to clinical trials or management guidelines for family members. The most common P/LP variants were in BRCA2 (30), CHEK2 (18) and ATM (17). Of positive men, 48% of positive men reported no family history of prostate, breast, ovarian or pancreatic cancer. In regards to self-reported ethnicity, 74% of the cohort was Caucasian, 16% Black, 5% Hispanic, 3% Asian and 2% Ashkenazi Jewish. Notably, 100% of positive variants identified in Black men were in DNA damage (10/14) or mismatch repair pathway (4/14) genes and therefore potentially actionable, compared to Caucasian men where 58% of positive variants were in these pathways (54/97 and 2/97, respectively).

Conclusion:

In an unselected mPCa patient population, we found an overall germline positive rate of 12%, consistent with the literature, including 7% with P/LP variants in HRR genes that qualify for FDA-approved therapies. Compared to other studies of mPCa patients, we tested a higher proportion of non-Caucasian, especially Black, men, all of whom had potentially actionable results. These data suggest that removing some barriers to testing, including cost, expands access to testing, especially in certain underserved populations, and could lead to better informed care for many more PCa patients and their families. 

Funding: N/A