Differential responses to taxanes and PARP inhibitors in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer.

PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions.

mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy.

Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35).

Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.

The Prostate. 2022 Nov 16 [Epub ahead of print]

Christopher T Su, Emily Nizialek, Jacob E Berchuck, Panagiotis J Vlachostergios, Ryan Ashkar, Alexandra Sokolova, Pedro C Barata, Rahul R Aggarwal, Rana R McKay, Neeraj Agarwal, Heather M McClure, Nellie Nafissi, Alan H Bryce, Oliver Sartor, Nicolas Sayegh, Heather H Cheng, Nabil Adra, Cora N Sternberg, Mary-Ellen Taplin, Marcin Cieslik, Ajjai S Alva, Emmanuel S Antonarakis

Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA., Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Department of Medicine, Weill Cornell Medical College, New York, New York, USA., Department of Medicine, Indiana University, Indianapolis, Indiana, USA., Department of Medicine, University of Washington, Seattle, Washington, USA., Department of Medicine, Tulane University, New Orleans, Louisiana, USA., Department of Medicine, University of California San Francisco, San Francisco, California, USA., Department of Medicine, University of California San Diego, San Diego, California, USA., Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA., Department of Hematology and Medical Oncology, Mayo Clinic, Phoenix, Arizona, USA., Rogel Cancer Center, Michigan Medicine, Ann Arbor, Michigan, USA.

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