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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 Condeduca,
  • 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,
  • Lavaud Pernelle,
  • 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

Publication: JAMA Network Open, October 2020

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.

Commented by Prof. Igor Tsaur

Platinum-based therapy for mCRPC patients with defect DDR genes

The recent advent of molecular selection tools for cancer patients prompted an advance in the biomarker-driven medicine for males with metastasised castration-resistant prostate cancer (mCRPC). Thus, somatic or germline deleterious aberrations in DNA Damage Response (DDR) genes, particularly in those critical for homologous recombination repair (HRR), have demonstrated to predict response to poly (ADP-ribose) polymerase (PARP) inhibition.

Encouraging results of the PROfound and TRITON2 trials paved the way for the Food and Drug Administration (FDA) to grant approval for olaparib and rucaparib to be administered to pre-treated men with mCRPC and HRR gene alterations (rucaparib limited to BRCA1 or BRCA2), which are encountered in 20-30% of the cases with advanced prostate cancer. Of note, platinum salts cause a replication fork collapse by inducing DNA crosslinks leading to synthetic lethality similar to PARP inhibitors which trap PARP on DNA. BRCA deficiency precludes HRR, enhancing both cell death and the response to these agents. Currently, little is known about the role of platinum-based protocols in this setting and it is a matter of high clinical interest.

Schmid et al. present a retrospective multicentre assessment of 508 mCRPC patients treated with platinum-based compounds as monotherapy. 80 men carried deficits in DDR genes, 98 were tested negative and the remaining 330 had no profiling available. PSA50 and soft-tissue response was 47.1% vs. 36.1% and 48.3% vs. 31.3% in positive vs. negative patients respectively, without reaching statistical significance. In the subgroup of 44 males with BRCA2 alterations, PSA50 and soft-tissue response was 63.9% and 50% respectively. Notably, this subgroup demonstrated the longest median overall survival of 15 mos. as compared to 4.1, 9.3 and 4.9 mos. in patients with BRCA1, ATM and other DDR gene aberrations respectively.

Interpretation of the findings of the study is hampered by, inter alia, inherent limitations due to its retrospective nature and particularly by differing platinum-based regimens, varying methods of molecular profiling, non-standardised patient selection, and missing data as well as small subgroup numbers. However, the authors of the study are generating a hypothesis for further research.

Platinum-based treatment appears to be beneficial for males with DDR gene defects, producing encouraging anticancer activity and warranting prospective trials with stratification into molecularly-defined subgroups. Selecting patients for specific treatment on the basis of predictive biomarkers is the ultimate goal in the landscape of mCRPC and identification of carriers of deficient DDR genes represents a light of hope at the end of the tunnel.