ASCO 2019: Outcomes of Men with Recurrent M0 Prostate Cancer who Defer Androgen Deprivation Therapy until Metastasis

Chicago, IL ( Optimal timing and criteria for implementation of androgen deprivation therapy (ADT) in men with relapsed M0 prostate cancer remains undefined. Early ADT induces the non-metastatic castration-resistant prostate cancer (nmCRPC) clinical state. The FDA approved apalutamide (SPARTAN1) and enzalutamide (PROSPER2) for nmCRPC based on prolongation of metastasis-free survival (MFS), which is now considered a valid endpoint for drug approval. Furthermore, the recent reporting of ARAMIS (darolutamide)3 at GU ASCO 2019 in this disease space has added a third therapeutic option to nmCRPC. Because overall survival (OS) in prostate cancer is usually long and long-term ADT is associated with irreversible adverse events and high costs, Catherine Marshall, MD, MPH, and colleagues from Johns Hopkins Hospital evaluated OS and other outcomes of men with relapsed prostate cancer and ADT deferred until metastasis. Their hypothesis for this study was that men who delayed hormone therapy until the time of metastases would also have long OS. 

This study included a retrospective review of 2,636 men who had a radical prostatectomy between 1981-2017 and developed biochemically recurrent prostate cancer from a single institution. Patients who received ADT prior to metastasis were excluded. Kaplan-Meier survival estimates of MFS and OS were defined from radical prostatectomy to event or censor. The authors also used multivariable Cox proportional hazards regression was used to identify prognostic factors. 

After excluding men inappropriate for this study, 1,686 men treated with deferred ADT until metastasis or censored metastasis-free were included. The median age was 60 years, median follow-up was 10 years (IQR 5-16), median prostate specific antigen (PSA) doubling time was 33 months (IQR <1-612), 78% had Gleason ≤7 disease, and 41% received salvage radiotherapy. The median metastasis-free survival (MFS) was 21 years (IQR 20-24) and median OS was 22 years (IQR 21-23). Among men with PSA doubling time ≤6 months (n=283), the median MFS was 9 years (IQR 8-10) and median OS was 13 years (IQR 11-15). Among men who developed metastasis (n=489), the median MFS was 10 years (IQR 9-11) and median OS was 15 years (IQR 14-17). Among men who developed metastasis and had a PSA doubling time ≤6 months (n=172), the median MFS was 6 years (IQR 6-8) and median OS was 10 years (IQR 9-12).
In multivariable models, age (HR 1.06, 95% CI 1.04-1.1), Gleason < 8 vs ≥8 (HR 0.4, 95% CI 0.3-0.5), radical prostatectomy stage (organ confined vs not HR 0.6, 95% CI 0.5-0.8), PSA doubling time (HR 0.995, 95% CI 0.993-0.997) and salvage radiation therapy (HR 0.88, 95% CI 0.81-0.96) were associated with OS. 

Dr. Marshall concluded this study with the following points:
  • Deferred ADT in relapsing M0 patients is associated with long OS measured from time of local treatment, comparable to OS with salvage ADT in contemporary experience
  • Drug approval trials in nmCRPC should focus on patients at high risk for metastasis and death prior to ADT, and determine standardized criteria for initiation of ADT
  • Prolongation of MFS in nmCRPC requires further validation and may not necessarily reflect a net OS benefit
Presented by: Catherine H. Marshall, MD, MPH, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD

Co-Authors: Wei Fu, Hao Wang, Bruce J. Trock, Mario A. Eisenberger; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; The Johns Hopkins University School of Medicine, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

  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.
  2. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med.2018 Jun 28;378(26):2465-2474.
  3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.