Platinum-based chemotherapy in metastatic prostate cancer with DNA repair gene alterations Journal Article
| Authors: | Mota, J. M.; Barnett, E.; Nauseef, J. T.; Nguyen, B.; Stopsack, K. H.; Wibmer, A.; Flynn, J. R.; Heller, G.; Danila, D. C.; Rathkopf, D.; Slovin, S.; Kantoff, P. W.; Scher, H. I.; Morris, M. J.; Schultz, N.; Solit, D. B.; Abida, W. |
| Article Title: | 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. © 2020 by American Society of Clinical Oncology |
| Keywords: | adult; cancer chemotherapy; cancer survival; treatment response; aged; unclassified drug; gene mutation; major clinical study; histopathology; monotherapy; conference paper; prostate specific antigen; dna repair; carboplatin; antineoplastic metal complex; protein; cohort analysis; brca1 protein; brca2 protein; retrospective study; docetaxel; atm protein; genomics; visceral metastasis; rad51 protein; castration resistant prostate cancer; germline mutation; fanconi anemia group a protein; human; male; priority journal; partner and localizer of brca2; cdk12 protein |
| Journal Title: | JCO Precision Oncology |
| Volume: | 4 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2020-04-16 |
| Start Page: | 355 |
| End Page: | 366 |
| Language: | English |
| DOI: | 10.1200/po.19.00346 |
| PROVIDER: | scopus |
| PMCID: | PMC7446522 |
| PUBMED: | 32856010 |
| DOI/URL: | |
| Notes: | Conference Paper -- Source: Scopus |
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