ASCO 2018: Association of Metastasis-Free Survival and Overall Survival in Non-Metastatic Castration-Resistant Prostate Cancer

Chicago, IL ( For diseases such as prostate cancer with a relatively long survival, even in advanced stages, survival outcomes (ie. PFS and OS) may take years to occur. The conduct of prostate cancer clinical trials is hampered by taking longer than a decade to reach the meaningful endpoint of OS and the fact that many men never die from prostate cancer, even if they relapse.

With the rapidly changing landscape of advanced prostate cancer therapy, intermediate clinical endpoints as surrogates for downstream survival outcomes are needed to inform clinical decisions, facilitate drug development, and develop subsequent clinical trials. The international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group reported that, based on individual patient data collected from 28 trials with 28,905 patients, metastasis-free survival (MFS) is a strong surrogate of OS in hormone-sensitive localized prostate cancer 1. Matthew Smith, MD, and colleagues presented results of their study assessing the relationship between MFS and OS in patients with non-metastatic CRPC (nmCRPC).

For this study, the authors used data from the phase III SPARTAN trial of men with high-risk nmCRPC2. The SPARTAN trial randomized 1207 men 2:1 to receive apalutamide vs placebo. In the planned primary analysis at 378 events, median 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 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 (time to metastasis, PFS, time to symptomatic progression, time to PSA progression, and PSA decline). Based on these results, apalutamide became the first FDA-approved treatment for patients with nmCRPC. Individual patient-level data from SPARTAN was used to undertake a landmark analysis for MFS. A Cox proportional hazard regression model, adjusted for covariates, evaluated the relationship of OS and development of metastases. The correlation of MFS and OS was assessed by Spearman’s and Fleischer’s correlation statistics.

A landmark analysis showed that patients who developed metastases at 6, 9, and 12 months had significantly shorter median OS compared with those patients without metastasis:

  • 6 months (n=105 patients with metastases): HR for OS 4.55 (95%CI 2.94-7.04)
  • 9 months (n=175 patients with metastases): HR for OS 5.39 (95%CI 3.61-8.06)
  • 12 months (n=230 patients with metastases): HR for OS 6.95 (95%CI 4.59-10.53)
Kaplan-Meier curves for 6 (a), 9 (b), and 12 (c) landmark analysis survival rates:
UroToday ASCO2018 Kaplan Meier curves

After adjusting for baseline covariates, the development of metastases remained associated with OS. A significant positive correlation was observed between MFS and OS (Spearman’s correlation coefficient: 0.62; p < 0.0001). The parametric Fleischer’s statistical model confirmed the positive correlation (coefficient: 0.69), with ~50% of the variability in OS explained by MFS.

Similar to MFS acting as a surrogate for OS among patients with localized prostate cancer, based on these results, MFS also acts as an appropriate surrogate for men with nmCRPC. This further justifies the FDA’s approval of apalutamide for men with nmCRPC based on MFS as a primary endpoint. MFS as a meaningful and valid intermediate clinical endpoint for OS should be strongly considered when designing future trials in this disease space. Clinical trial information: NCT01946204

  1. Xie W, Regan MM, Buyse M, et al. Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol 2017;35(27):3097-3104.
  2. 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.

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

Co-Authors: Maneesha Mehra, Sandhya Nair, Joe Lawson, Eric Jay Small; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA; Janssen Research & Development, Raritan, NJ; 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, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

Read More: 
First Presentation - SPARTAN: A Study of Apalutamide (ARN-509) in Men with Non-Metastatic Castration-resistant Prostate Cancer
Watch: First presentation of SPARTAN - a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) - Eric Small