Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations
Authors: Sabine Schmid, Aurelius Omlin, Celestia Higano, Christopher Sweeney, Nieves Martinez Chanza, Niven Mehra, Malou C. P. Kuppen, Himisha Beltran, Vincenza Conteduca, Daniel Vargas Pivato de Almeida, Fernando Cotait Maluf, William K. Oh, Che-Kai Tsao, Oliver Sartor, Elisa Ledet, Giuseppe Di Lorenzo, Steven M. Yip, Kim N. Chi, Diletta Bianchini, Ugo De Giorgi, Aaron R. Hansen, Tomasz M. Beer, Pernelle Lavaud, Rafael Morales-Barrera, Marcello Tucci, Elena Castro, Kostas Karalis, Andries M. Bergman, Mo Linh Le, Ursina Zürrer-Härdi, Carmel Pezaro, Hiroyoshi Suzuki, Andrea Zivi, Dirk Klingbiel, Sämi Schär, Silke Gillessen
Journal: JAMA Network Open (2020)

<h3>Importance</h3> DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition or platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown. <h3>Objective</h3> To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations. <h3>Design, Setting, and Participants</h3> In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019. <h3>Exposure</h3> Treatment with platinum-based compounds either as monotherapy or combination therapy. <h3>Main Outcomes and Measures</h3> The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations. <h3>Results</h3> A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (<i>P</i> = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (<i>P</i> = .07). In the subgroup of 44 patients with<i>BRCA2 </i>gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively. <h3>Conclusions and Relevance</h3> In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.