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ASCO 2018

ASCO 2018: Relationship of Time to Metastasis and Site of Metastases in Patients with Nonmetastatic CRPC: Results from the Phase 3 SPARTAN Trial

Chicago, IL (UroToday.com) In February 2018, apalutamide became the first FDA-approved treatment for patients with non-metastatic CRPC (nmCRPC). Apalutamide is a nonsteroidal anti-androgen AR inhibitor, which binds to the ligand-binding domain of the AR. Presented at GU ASCO 2018 and published in the New England Journal of Medicine1 the SPARTAN trial randomized 1,207 men 2:1 to receive apalutamide vs placebo. In the planned 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). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group.

The conclusions from SPARTAN were 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 consistent across all subgroups, and the results were supported by consistent improvement across all evaluable endpoints, including: (i) time to metastasis, (ii) PFS, (iii) time to symptomatic progression, (iv) time to PSA progression, and (v) PSA decline. Based on the 72% relative risk reduction of distant metastasis for men taking apalutamide, Dr. Matthew Smith and colleagues assessed the relationship between time-to-metastasis and site of metastases after androgen deprivation therapy (ADT) plus apalutamide or placebo at the ASCO 2018 annual meeting.

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
Time-to-metastasis was defined as time from randomization to first evidence of blinded central review–confirmed radiographically detectable distant metastasis. Metastases were assessed by site of metastases, including (i) nodal (M1 nodes + soft tissue), (ii) bone (bone ± M1 nodes), and (iii) visceral (visceral, regardless of other sites). Kaplan-Meier methods were used to analyze time-to-metastasis, and a stratified proportional hazards model with treatment group as a factor, stratified by PSADT, bone-sparing agent use, and loco-regional disease, was used to estimate the hazard ratio for time-to-metastases.

The summary of the patients that developed metastases is as follows:

  • Nodal: apalutamide 30% (52/175) vs placebo 40% (76/191)
  • Bone: apalutamide 57% (100/175) vs placebo 52% (100/191)
  • Visceral: apalutamide 13% (23/175) vs placebo 8% (15/191)
Assessing time-to-metastases for apalutamide vs placebo, the HR in the intent-to-treat population was 0.27 (95%CI 0.22-0.34), 0.19 (95%CI 0.13-0.27) for nodal metastases, 0.31 (95%CI 0.23-0.41) for bone metastases, and 0.51 (95%CI 0.26-0.99) for visceral metastases.

In addition to the remarkable 72% reduction in risk of metastases that gained apalutamide FDA approval for the treatment of men with nmCRPC, the results from the current study solidify that apalutamide markedly decreased the risk of time to metastases regardless of the site of metastasis. Dr. Smith concluded that the consistency of these results provides further evidence for the clinical benefit of apalutamide in men with nmCRPC. 

Clinical trial information: NCT01946204

Presented by: Matthew R. Smith, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA

Co-Authors: Fred Saad, Dana E. Rathkopf, Boris A. Hadaschik, Simon Chowdhury, Margaret K. Yu, Angela Lopez-Gitlitz, Oliver Brendan Rooney, Mohamed Darif, Eric Jay Small; 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, San Diego, CA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA

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

WATCH: Erc Small Present: SPARTAN - a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) 

Reference:

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.