Barcelona, Spain (UroToday.com) The SPARTAN study is a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial investigating the efficacy and safety of apalutamide (APA) in men with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Patients with nmCRPC were randomized to APA + androgen deprivation therapy (ADT) or placebo (PBO) + ADT. Initial published analysis with a median follow-up of 20.3 months showed a 72% reduction in the risk of metastasis for patients receiving APA + ADT compared to those receiving PBO + ADT.1 This finding led to FDA approval of APA + ADT for men with nmCRPC in February 2018. Dr. Smith presented updated results, focused on the effect of APA on overall survival (OS), as well as time to chemotherapy, PFS2 (defined as time of study entry to progression on subsequent treatment), and safety.
Eligible patients (N=1207) were randomized 2:1 to APA + ADT or PBO + ADT. Patients who developed distant metastases were eligible for subsequent therapy including with abiraterone + prednisone. The primary outcome measure of the trial is metastasis-free survival (MFS) defined from the time of randomization to the first bone or soft tissue metastasis on bone scan, CT or MRI scan performed throughout the study, or death due to any cause. Secondary outcomes include time to metastasis, progression-free survival (PFS) and PFS2, time to symptomatic progression, overall survival (OS), time to initiation of cytotoxic chemotherapy, and incidence of treatment-emergent adverse events (TEAEs) were evaluated.
Some notable inclusion criteria include adult men with adenocarcinoma of the prostate without neuroendocrine or small cell features, prostate-specific antigen (PSA) doubling time of <= 10 months, castrate levels of testosterone, at least a 4-week washout period following treatment with first-generation anti-androgen therapy (e.g. bicalutamide), at least a 5-week washout period after 5-alpha reductase inhibitors or estrogens, at least 4 weeks from major surgery or radiation therapy, and ECOG 0 or 1. Notable exclusion criteria include confirmed distant metastases, prior treatment with second-generation anti-androgens, prior chemotherapy, and various existing medical conditions including other malignancies and heart disease.
In the previously-reported planned primary analysis, the addition of APA improved OS (HR 0.70, p = 0.07), though the OS data was immature; 104 of 427 events needed for the planned OS analysis (24%) had been observed at that time.1 The updated OS data presented by Dr. Smith is after 285 events.
With a median follow-up of 41.0 months, the addition of APA is associated with a 25% reduction in risk of death (HR 0.75, p = 0.197); this did not meet the pre-specified significance cut off of 0.0121. The four-year OS rates for men treated with APA + ADT were 72.1% compared to 64.7% in the PBO + ADT cohort; this effect was consistent across all subgroups analyzed.
Similarly, the addition of APA was associated with a 40% reduction in rates of chemotherapy initiation. 69% of men treated on the control arm received subsequent life-prolonging therapy during the study period compared to only 40% of those treated with APA. The addition APA also significantly prolonged PFS2 from 43.8 months to 55.6 months (HR 0.55, p < 0.0001).
There was no significant change in TEAEs. Serious TEAEs were observed in 33.5% of men receiving APA + ADT and 24.9% receiving PBO + ADT, similar to previous reports.
In conclusion, the addition of APA to ADT is associated with a 25% reduction in death compared to PBO in men with high-risk nmCRPC, however, this is a premature analysis with only 67% of the planned events occurring and did not achieve the pre-specified significance threshold. This updated analysis does, however, demonstrate significant improvement in time to chemotherapy and PFS2, further supporting APA + ADT as a standard option for men with high-risk nmCRPC.
Presented by: Matthew R. Smith, M.D., Ph.D., Director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, Boston, Massachusetts
Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute (Twitter: @jberchuck) at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain