The oncological benefits of PCa treatment have long been studied using randomized controlled trials (RCTs) with the primary endpoint of overall survival (OS). However, these trials are often limited by 1) the long follow-up that is required to demonstrate the benefit of a novel therapy or given approach, 2) the costs associated with the trial, and 3) the prolonged time to study publication, which may render the results out of date by the time of their release. One possible solution is to define intermediate clinical endpoints (ICEs), which can be used as potential surrogates for overall survival (OS). In fact, metastasis-free survival has been shown to be a robust surrogate for OS in men with non-metastatic PCa.3 However, this surrogate only holds true for a select subset of patients, and leaves those trials analyzing metastatic disease at a significant disadvantage.
In an effort to address this point, we analyzed potential surrogates for predicting overall survival in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
Using patients enrolled in the CHAARTED trial, we investigated three different ICEs within six and 12 months as potential surrogates, including PSA response, progression, and development of castration-resistant prostate cancer state (CRPC). Progression was defined as either castration-resistant status or clinical progression. A documented clinical or serologic progression with a testosterone level less than 50 ng/dl denoted castration-resistant status; whereas clinical progression was defined as increasing symptoms of bone metastasis; progression according to the response evaluation criteria in solid tumors (Version 1.0); or clinical deterioration due to cancer according to the investigator’s opinion. Time to any event was considered from the time of randomization.
Briefly, we used data from 790 patients with mHSPC who were enrolled in the CHAARTED trial from July 2006 to December 2012. Of these, 393 (49.7%) received androgen deprivation therapy (ADT) alone, while 397 (50.3%) received combination therapy. Four out of the six ICEs (progression within 6 and 12 months and development of CRPC within 6 and 12 months) satisfied all Prentice criteria and were considered for surrogacy.4 In order to discriminate the best surrogate, we evaluated the proportion of the treatment effect (PTE) explained by the surrogate. In short, the PTE ranges from 0 to 1, where 1 represents the perfect surrogate, and 0 is regarded as a lack of surrogacy.5 Theoretically, the best possible surrogate is the one that can explain 100% of the outcome, and therefore a PTE of one or 100%. The PTEs in our analysis were 88%, 52%, 80%, and 46% for progression within six months, progression within 12 months, development of CRPC within six months, and development of CRPC within 12 months, respectively.
From these data, we found that progression within six months following therapy with ADT and docetaxel for mHSPC represents a strong surrogate for OS. We feel that this information has several important clinical implications: first, it can be used for patient counseling for individuals who have progressed within the first six months of treatment. Second, it can be used for early identification of those individuals who might benefit from second-line treatments or might be enrolled in trials aimed at evaluating the role of novel therapies.
According to our study, among the patients that were alive and not censored six months after randomization and did progress on treatment, the survival rate was almost one-fourth after two years.6 The prompt administration of second-line therapies or the exploration of novel medications for this patient category might potentially translate to a survival benefit for this patient population.
Written by: John Pfail, MD,1 and Alberto Martini, MD, 2 MD
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York
- Department of Urology, Vita-Salute San Raffaele University, Milan, Italy
- Siegel, Rebecca L., Kimberly D. Miller, and Ahmedin Jemal. "Cancer statistics, 2020." CA: A Cancer Journal for Clinicians 70, no. 1 (2020): 7-30.
- Weiner, A. B., R. S. Matulewicz, S. E. Eggener, and Edward Matthew Schaeffer. "Increasing incidence of metastatic prostate cancer in the United States (2004–2013)." Prostate cancer and prostatic diseases 19, no. 4 (2016): 395-397.
- Xie, Wanling, Meredith M. Regan, Marc Buyse, Susan Halabi, Philip W. Kantoff, Oliver Sartor, Howard Soule et al. "Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer." Journal of Clinical Oncology 35, no. 27 (2017): 3097.
- Prentice, Ross L. "Surrogate endpoints in clinical trials: definition and operational criteria." Statistics in medicine 8, no. 4 (1989): 431-440.
- Parast, Layla, Mary M. McDermott, and Lu Tian. "Robust estimation of the proportion of treatment effect explained by surrogate marker information." Statistics in medicine 35, no. 10 (2016): 1637-1653.
- Martini, Alberto, John Pfail, Francesco Montorsi, Matthew D. Galsky, and William K. Oh. "Surrogate endpoints for overall survival for patients with metastatic hormone-sensitive prostate cancer in the CHAARTED trial." Prostate Cancer and Prostatic Diseases (2020): 1-8.