AUA 2020: Surrogate Endpoints for Overall Survival for Patients with Metastatic Hormone-Sensitive Prostate Cancer in the CHAARTED Trial

( Prostate cancer is the most commonly diagnosed male malignancy, developing in one out of nine men during their lifetime. Metastasis free survival has been shown to be a robust surrogate for overall survival in men with non-metastatic prostate cancer. However, this surrogate only holds true for a select subset of patients and leaves those trials analyzing metastatic disease at a disadvantage.

The authors of this study aimed to identify potential surrogates for predicting overall survival in patients with metastatic hormone-sensitive prostate cancer. Additionally, they planned to evaluate potential surrogates and identify the best one for overall survival.

For the purpose of this study, 790 patients with metastatic hormone-sensitive prostate cancer were enrolled in the CHAARTED trial from July 2006 to December 2012. Patients were randomized to receive either ADT alone or ADT plus docetaxel chemotherapy for six cycles. The primary outcome was overall survival. Three different intermediate clinical endpoints were investigating as well, within 6 and 12 months as surrogates. These included PSA response, progression, and development of the castrate-resistant state. To distinguish the best surrogate, the authors evaluated the proportion of the treatment effect explained by the surrogate. The intermediate clinical endpoints were evaluated for surrogacy using the Prentice criteria:

  • Intervention should affect the distribution of the endpoint
  • intervention should affect the distribution of a surrogate
  • the intervention of the endpoint should depend on surrogate
  • the surrogate should fully account for the impact of the intervention on the endpoint

The proportion of treatment effect for the four surrogates that met the fourth criterion, which was:

  • 88%progression within 6 months
  • 52% progression within 12 months
  • 80% development of CRPC within 6 months
  • 46% development of CRPC within 12 months

When assessing patients who are alive and not censored after six months following randomization, this survival probability at one and two years after this landmark point was 57% and 28% for those who progressed in the prior six months versus 94% and 80% for the rest of the patient population.

A total of 4/6 evaluated intermediate-risk endpoints met all the Prentice criteria for surrogacy:

  • Progression within six months (HR 5.7, 95% CI 4.26-7.64, p<0.001)
  • progression within 12 months (HR 7.09, 95% CI 5.16-9.76, p<0.001)
  • development of CRPC within 6 months (HR 5.11, 95% CI 3.81-6.85, p<0.001)
  • development of CRPC within 12 months (HR 6.24, 95% CI 4.58-8.51, p<0.001)

Progression within six months following combination therapy was demonstrated to be the best surrogate for overall survival (proportion of treatment effect of 88%).

The authors concluded that progression within six months following therapy with ADT and docetaxel for metastatic hormone-sensitive prostate cancer represents a strong surrogate for overall survival. This surrogate can serve many purposes and can aid in the design of future studies. This subgroup of patients might be considered for receiving second-line therapies or be enrolled in trials evaluating the role of novel medications

Presented by: John Pfail, Jr., Icahn School of Medicine at Mount Sinai, New York, NY

Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHanan at the 2020 American Urological Association (AUA) Annual Meeting, Virtual Experience #AUA20, June 27- 28, 2020
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