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Prostate Cancer Patients With DNA Damage Repair Mutations May Respond to Platinum Chemo

NEW YORK – A subset of patients with metastatic castration-resistant prostate cancer (mCRPC) who harbor DNA damage repair (DDR) gene mutations may have an improved response to platinum chemotherapy compared to those without such mutations, according to a study recently published in the Journal of Clinical Oncology: Precision Oncology.

The findings were based on a retrospective analysis of a cohort of patients with prostate cancer who had undergone tumor and germline genomic sequencing on Memorial Sloan Kettering's MSK-IMPACT test, and who went on to receive platinum-based chemotherapy between Oct. 1, 2013 and July 30, 2018.

The group of researchers, led by MSK's Jose Mota, then evaluated these patients' responses based on their DDR status. Patients were considered to have DDR if they harbored a deleterious somatic alteration or a pathogenic germline alteration in a gene associated with a DNA repair pathway, including BRCA1, BRCA2, CDK12, FANCA, PALB2, and ATM.

Out of an initial group of 140 patients, the researchers first focused on 64 patients who had not received a PARP inhibitor and who were taxane refractory prior to starting platinum chemotherapy. Of these, 64 patients, or 25 percent, had DDR mutations, and 75 percent were DDR wildtype — a distribution that the authors noted reflected that of larger datasets.

In 56 patients, researchers explored whether DDR status was associated with declines in prostate-specific antigen levels, which is a surrogate measure of platinum response in mCRPC trials. They reported that 23 percent of patients achieved a 50 percent decline in PSA levels from baseline after treatment with platinum chemotherapy, and this response was more common among the group harboring DDR mutations.

Specifically, 50 percent of the patients harboring DDR mutations achieved this response compared with 13 percent of the DDR wildtype patients. In the DDR mutated response group, patients had mutations in BRCA, PALB2, FANCA, and CDK12.

However, none of the patients who harbored ATM mutations responded to platinum chemotherapy. Notably, the researchers also did not find a significant difference in overall survival between the DDR-mutated and DDR-wildtype groups.

The researchers also evaluated responses to platinum chemotherapy among patients whose cancer had progressed after treatment with one of the PARP inhibitors with breakthrough therapy designation from the US Food and Drug Administration for BRCA1/2- or ATM-mutated mCRPC. Out of eight patients who fit this bill, three derived some clinical benefit from platinum-based chemotherapy, although the researchers noted that "outcomes in this advanced patient population were generally poor." Patients in this group with ATM mutations also did not respond to platinum-based chemo and progressed rapidly.  

"[The findings] reinforce the need for novel therapeutic approaches for the approximately 4 percent of patients with mCRPC who harbor deleterious alterations in ATM," wrote Mota and colleagues, adding the caveat that the very small sample size of the present study necessitates confirmation in larger cohorts.