ASCO GU 2018: Comparative Assessment of Abiraterone or Enzalutamide Activity in the PROREPAIR-B Study

San Francisco, CA (UroToday.com) Dr. Lozano and colleagues presented their comparative assessment of abiraterone or enzalutamide activity in the PROREPAIR-B study. Germline mutations in DNA repair genes have been associated with poor prostate cancer outcomes in retrospectives studies [1,2]; these defects have been identified in 12% of mCRPC patients [3]. Germline and somatic DNA damage repair defects (DDR) have been correlated with response to platinum-based chemotherapy and PARP inhibitors [4,5], but no conclusive data are available with regards to currently approved therapies for mCRPC. As such, the objective of this study was to assess the outcomes of mCRPC patients in the PROREPAIR-B study using currently approved, standard treatment agents, abiraterone or enzalutamide.

PROREPAIR-B (NCT03075735) is a prospective, multi-center observational cohort study. Patients diagnosed with mCRPC, with unknown mutational status at study entry and who were going to start a first-line treatment for mCRPC were eligible. For this sub-analysis, patients who received abiraterone or enzalutamide as first androgen receptor targeted therapy were selected. The endpoints of this sub-analysis assessed the impact of BRCA1BRCA2ATMPALB2 and other germline mutations in DNA repair genes on cause-specific survival (CSS), progression-free survival (PFS), time to PSA progression and response to the first androgen receptor targeted therapy received as 1st or 2nd line therapy.

There were 365 patients eligible for this analysis and 57 validated germline DDR defects were detected among these patients (15.6% prevalence). CSS from mCRPC was not significantly different between germline DDR defect carriers and non-carriers. However, CSS from mCRPC in BRCA2 carriers was significantly shorter than in non-carriers (17.5 vs 33.1 months, p = 0.02). CSS from first androgen receptor targeted therapy, PFS and response-rates were not significantly different between both groups. However, time to PSA progression was shorter in patients who were BRCA2 carriers (2.9 vs 7.0 months, p = 0.118), as was PFS (4.2 vs 9.1 months, p = 0.064). On multivariable analysis, BRCA2 was not prognostic for CSS, however elevated LDH, hemoglobin <10 mg/dL and albumin <3.5 g/dL were independent predictors of CSS. 

The authors concluded that this is the first study to prospectively follow-up DNA repair germline mutations to determine clinical outcomes of standard treatment for mCRPC. There was a trend to a short cancer-specific survival, time to PSA progression, and progression-free survival from first androgen signaling inhibitor in BRCA2 carriers. The results suggest that different germline DDR defects may have a distinctive impact on mCRPC outcomes. 


Presented by: Rebeca Lozano, MD Spanish National Cancer Research Centre, Madrid, Spain

Co-Authors: Nuria Romero-Laorden, Angela del Pozo, Ana Medina, Maria Jose Mendez, Rafael Morales Barrera, Aranzazu Aranzazu Gonzalez del Alba, Alejo Rodriguez-Vida, Amaia Hernandez, Juan Carlos Silla-Castro, Sergio Vazquez, Belen Gonzalez, Alvaro Pinto, Jose Luis Perez Gracia, Rosa Querol, Vanessa Cañadilla, Montserrat Domenech, Colin Pritchard, Elena Castro, David Olmos

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA


References: 

1. Na R, Zheng SL, Han M, et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur Urol. 2017;71(5):740-747.

2. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757.

3. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453.

4. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708.

5. Cheng HH, Pritchard CC, Boyd T, et al. Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur Urol. 2016;69(6):992-995.
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