Platinum-Based Chemotherapy in Metastatic Prostate Cancer With DNA Repair Gene Alterations

Abstract

PURPOSE Alterations in DNA damage repair (DDR) genes occur in up to 25% of patients with metastatic castration-resistant prostate cancer (mCRPC) and may sensitize to platinum chemotherapy. We aimed to evaluate the efficacy of platinum-based chemotherapy in DDR-mutant (DDRmut) mCRPC. METHODS We assessed response to platinum chemotherapy based on DDR gene alteration status in men with mCRPC who underwent tumor and germline genomic profiling. Patients with deleterious alterations in a gene panel that included BRCA2, BRCA1, ATM, PALB2, FANCA, and CDK12 were considered DDRmut. RESULTS A total of 109 patients with mCRPC received platinum-based chemotherapy between October 2013 and July 2018. Sixty-four of 109 patients were taxane refractory and poly (ADP-ribose) polymerase inhibitor (PARPi) naïve. Within this subset, DDRmut was found in 16/64 patients (25%) and was associated with an increased likelihood of achieving a prostate-specific antigen (PSA) decline of 50% or more from baseline (PSA50; odds ratio, 7.0; 95% CI, 1.9 to 29.2). Time on platinum chemotherapy tended to be longer in the DDRmut group (median, 3.0 v 1.6 months; hazard ratio, 0.55, 95% CI, 0.29 to 1.24). No difference in survival was detected. Of 8 patients with DDRmut disease who received platinum-based therapy after a PARPi, 3/7 evaluable patients had radiographic partial response or stable disease, and 2/7 had a PSA50 response. None of 4 patients with ATM mutations had platinum responses regardless of prior PARPi exposure. CONCLUSION Patients with DDRmut disease had better response to platinum-based chemotherapy, suggesting that DDR status warrants prospective validation as a potential biomarker for patient selection. Responses to platinum chemotherapy were observed in BRCA-altered prostate cancer after PARPi progression. Additional studies are needed to determine the predictive role of individual genes on platinum sensitivity in the context of other clinical and genomic factors.

Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

“…40,41 In the DDR context, several retrospective studies suggest that BRCA2-mutated prostate cancer patients might benefit from this treatment approach. [42][43][44][45] The largest of these analyses included 141 men with mCRPC treated with carboplatin and docetaxel at the Dana Farber Cancer Institute between 2001 and 2015, and reported a benefit from this combination for patients with germline BRCA2 mutations. 43 Six out of the eight BRCA2 carriers (75%) showed a >50% decline in the levels of prostate-specific antigen (PSA) at 12 weeks, compared with 23 of 133 of non-carriers (17%) (P = 0.001).…”

Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

“…DDRd, and particularly genes associated with homologous recombination, are suggested as plausible biomarkers for platinum responses in mCRPC 10 . A recent study by Mota et al described a higher proportion of PSA 50 responses to platinum‐based chemotherapy in the DDRd group when compared to DDRp patients 11 . In our study, a similar outcome was found, although the biochemical response of DDRd patients to carboplatin was largely driven by the BRCA2mut subgroup, with all seven BRCA2mut patients showing a PSA 50 response.…”

“…[8][9][10] A recent study demonstrated biochemical responses in half of the patients with DDRd, particularly those with BRCA2 aberrations, as well as those with alterations in PALB2, FANCA or CDK12. 11 Patients with small cell (neuroendocrine) prostate cancer (SC-NEPC) appear to show superior disease control with platinum-based regimens over standard of care taxane chemotherapy for mCRPC. 12,13 A recent study identified patients with aggressive variant prostate cancer (AVPC), as a subtype defined as either SC-NEPC or prostate adenocarcinoma with clinicopathological features associated with poor outcome, to benefit most from platinum-based regimens.…”

“…In patients with DDRd tumours, multiple retrospective studies and case series have shown clinical meaningful responses to platinum compounds 8‐10 . A recent study demonstrated biochemical responses in half of the patients with DDRd, particularly those with BRCA2 aberrations, as well as those with alterations in PALB2 , FANCA or CDK12 11 . Patients with small cell (neuroendocrine) prostate cancer (SC‐NEPC) appear to show superior disease control with platinum‐based regimens over standard of care taxane chemotherapy for mCRPC 12,13 .…”

The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer

“…Radium-223 is not included due to the recent EMA recommendations restricting its use only to mCRPC patients who already received two treatments. Carboplatin is included despite the lack of an indication for prostate cancer since there is accumulating evidence that platinum-based chemotherapy is effective in tumors with defects in the DNA repair genes [26]. Several therapies will be available for treatment of patients in a biomarker signature, and-conversely-a given as well as one treatment can be administrated for patients with different biomarker signatures.…”