ASCO 2020: Final Survival Results from SPARTAN, A Phase III Study of Apalutamide versus Placebo in Patients with Nonmetastatic Castration-Resistant Prostate Cancer

(UroToday.com) There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients. These agents, as well as darolutamide, were subsequently approved on the basis of demonstrated improvements in metastasis-free survival. While metastasis-free survival has been shown to be a reasonable surrogate for overall survival in this population, there were questions as to whether the benefit of using androgen-axis inhibitors would translate to overall survival benefits, in part due to the differential survival effect seen according to disease burden in CHAARTED. In September 2019, update analysis of SPARTAN was presented at ESMO and simultaneously published demonstrating an overall survival benefit to the use of apalutamide, as compared to placebo, in men with non-metastatic castration-resistant prostate cancer. However, as a result of the use of sequential outcome testing, the observed effect (hazard ratio 0.75, 95% confidence interval 0.59 to 0.96, p=0.0197) did not meet the pre-specified p-value threshold determined from the O’Brien-Fleming method (threshold of 0.0121).

In the Poster Discussion section of the 2020 American Society of Clinical Oncology Virtual Annual Meeting, Dr. Small and colleagues presented updated overall survival data assessing apalutamide in non-metastatic castration-resistant prostate cancer from SPARTAN.

The methodology of the SPARTAN trial has been previously described in both presentations and publications. In short, 1207 patients with non-metastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of ≤ 10 months were randomized in a 2:1 fashion to apalutamide 240mg daily or placebo, in addition to continuing androgen deprivation therapy.

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As previously published, SPARTAN demonstrated a significant improvement in metastasis-free survival and a statistically non-significant improvement in overall survival. As a result of meeting the primary outcome endpoint, patients in the SPARTAN trial were unblinded and patients randomized to placebo who had not progressed were offered apalutamide cross-over. After initial analysis meeting the primary outcome of metastasis-free survival, 76 patients receiving placebo crossed-over and receiving apalutamide. At the time of progression, patients could receive open-label sponsor-provided abiraterone acetate + prednisone, or other anti-neoplastic therapies.

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Overall survival and time to cytotoxic chemotherapy were tested by group sequential testing procedure with O’Brien-Fleming (OBF)-type alpha spending function. Median overall survival was assessed using the Kaplan Meier technique and associated hazard ratios, with 95% confidence intervals, were calculated using Cox proportional hazard models. A sensitivity analysis for overall survival, accounting for crossover using a naïve censoring approach, was conducted.

Median follow-up at the time of data cut-off was 52 months. At this time, 428 (of a required 427) deaths had occurred to allow for analysis. As would be expected from the previously published analysis of the primary outcome (metastasis-free survival), median duration of treatment was longer for patients receiving apalutamide (32.9 months) compared to those receiving placebo (11.5 months).

Median overall survival was significantly longer among men receiving apalutamide than placebo (73.9 versus 59.9 months), corresponding to a relative reduction of 21.6% in the risk of death (hazard ratio 0.784, p-value 0.0161; OBF threshold of 0.046 for statistical significance). Results were similar in the sensitivity analysis accounting for cross-over and when assessing time to cytotoxic chemotherapy (Table).

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The adverse event profile at this analysis was consistent with the previous reports from the SPARTAN cohort.

Thus, this third and final analysis of the SPARTAN cohort demonstrates a statistically significant improvement in overall survival for patients receiving apalutamide for non-metastatic castration-resistant prostate cancer.

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Presented by: Eric Jay Small, MD, FASCO, Professor of Medicine, Department of Medicine/Division of Hematology/Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA.

Co-Authors: Fred Saad, Simon Chowdhury, Stephane Oudard, Boris A. Hadaschik, Julie N Graff, David Olmos, Paul N. Mainwaring, Ji Youl Lee, Hiroji Uemura, Peter De Porre, Andressa Smith, Sabine Doris Brookman-May, Susan Li, Ke Zhang, Oliver Brendan Rooney, Angela Lopez-Gitlitz, Matthew Raymond Smith

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.

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