Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations

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 GiorgiAaron 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

Research output: Contribution to journalArticlepeer-review

Abstract

Importance: 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 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.

Objective: To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations.

Design, Setting, and Participants: 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.

Exposure: Treatment with platinum-based compounds either as monotherapy or combination therapy.

Main Outcomes and Measures: 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.

Results: 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 (P = .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 (P = .07). In the subgroup of 44 patients with BRCA2 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.

Conclusions and Relevance: 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.

Original languageEnglish
Pages (from-to)e2021692
JournalJAMA network open
Volume3
Issue number10
DOIs
Publication statusPublished - Oct 1 2020

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents/therapeutic use
  • DNA Repair-Deficiency Disorders/drug therapy
  • Docetaxel/therapeutic use
  • Drug Therapy/methods
  • Humans
  • Male
  • Middle Aged
  • Paclitaxel/therapeutic use
  • Platinum Compounds/therapeutic use
  • Prostatic Neoplasms/therapy
  • Retrospective Studies

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