ASCO 2018: Predicting Disease Progression in Patients with Nonmetastatic CRPC: Analysis from the Phase 3 SPARTAN Trial

Chicago, IL (UroToday.com)  Men with non-metastatic CRPC (nmCRPC) and PSA doubling time (PSADT) of ≤ 10 months are at high risk for metastatic disease and associated death. Apalutamide is a next-generation androgen receptor inhibitor, which binds to the ligand-binding domain of the AR. AR inhibition is secondary to nuclear translocation and DNA binding, with 7-10 fold higher affinity than bicalutamide. Presented at the 2018 GU ASCO meeting and published in the New England Journal of Medicine [1], the SPARTAN trial randomized 1207 men 2:1 to receive apalutamide vs placebo. 

In the primary analysis at 378 events, median metastasis-free survival (MFS) was 40.5 months in the apalutamide group compared with 16.2 months in the placebo group (HR for metastasis or death 0.28, 95% CI 0.23-0.35). Time to symptomatic progression was significantly longer with apalutamide than with placebo (HR 0.45, 95%CI 0.32-0.63). Results from the SPARTAN trial demonstrated that apalutamide decreased the risk of metastasis or death by 72% and prolonged the median MFS by more than two years in men with high-risk nmCRPC. Furthermore, the MFS benefit was supported by consistent improvement across all evaluable endpoints: time to metastasis, PFS, time to symptomatic progression, time to PSA progression, and PSA decline. At  2018 ASCO annual meeting, Dr. Small and colleagues presented results of their post-hoc analysis of SPARTAN, assessing predictors of clinical endpoints among men with nmCRPC. 

Key inclusion criteria for men enrolling in SPARTAN included: 
  • Histologically confirmed adenocarcinoma of the prostate, castration-resistant 
  • High risk of developing metastasis: PSA doubling time of 10 months or less during continuous ADT 
  • Negative bone scan and CT of the pelvis, abdomen, chest, and head 
For this study, the authors used a non-stratified proportional hazards model to assess predictors of clinical end points, examining the following covariates: (i) treatment received, (ii) PSADT, (iii) use of bone-sparing agents, (iv) N0 vs N1 at study entry, (v) ECOG performance status, (vi) prior therapies, (vii) Gleason score, (viii) age, and (ix) baseline PSA. 

Among the 1207 patients included in SPARTAN (n=806 apalutamide; n=401 placebo), a relationship between shorter PSADT and faster time to metastasis or death was observed in the placebo arm:  
Screen Shot 2018 06 02 at 10.43.44 PM

The following covariates were independent predictors of longer MFS for the combined arms analysis:  
  • Apalutamide treatment: HR 0.26 (95%CI 0.21-0.32) 
  • PSADT > 6 months: HR 0.65 (95%CI 0.51-0.84) 
  • N0 disease: HR 0.68 (95%CI 0.52-0.89) 
  • Gleason score at diagnosis ≤ 7: HR 0.75 (95%CI 0.61-0.92) 
  • Baseline PSA ≤ 7.8 ng/mL: HR 0.59 (95%CI 0.47-0.73) 
Non-significant predictors of metastasis included ECOG PS (0 vs 1; p=0.154), use of bone-sparing agents (p=0.174), prior hormonal therapies (≥2 vs 1; p=0.406), and age (p=0.0784). 

Even when adjusting for clinical predictors of MFS, apalutamide maintained a 74% risk of reduction for MFS, consistent with a similar magnitude of risk reduction as noted in the primary analysis (72% risk reduction). This study also highlights several other clinical predictors of metastasis, including PSADT, N0 disease, Gleason score, and baseline PSA. 

Clinical trial information: NCT01946204 

Presented By: Eric J. Small, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 
Co-Authors: Fred Saad, Dana E. Rathkopf, Boris A. Hadaschik, Simon Chowdhury, Margaret K. Yu, Angela Lopez-Gitlitz, Oliver Brendan Rooney, Youyi Shu, Mohamed Darif, Matthew Raymond Smith; Centre Hospitalier de l’Université de Montréal/CRCHUM, University of Montréal, Montréal, QC, Canada; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; University of Duisburg-Essen, Essen, Germany; Guy's, King's and St Thomas' Hospitals, London, United Kingdom; Janssen Research & Development, Los Angeles, CA; Janssen Research & Development, High Wycombe, United Kingdom; Janssen Research & Development, Collegeville, PA; Janssen Research & Development, San Diego, CA; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md  at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

References: 
1. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378(15):1408-1418.
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