Despite advances in treatment, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease, with a median survival of approximately 2.5 years. mCRPC can develop from either metastatic hormone-sensitive prostate cancer, or from nonmetastatic prostate cancer that has developed resistance to androgen deprivation therapy (ADT). Since metastases are a major cause of complications and death in men with prostate cancer, prevention of metastases is an important treatment goal in patients with nonmetastatic CRPC (nmCRPC). However, there are currently no approved treatments to either prevent or delay development of metastatic disease. Men with nmCRPC who have a prostate-specific antigen (PSA) doubling time of less than 8 to 10 months while on ADT are at high risk of metastatic disease progression. In a phase II trial in this patient population, treatment with the novel nonsteroidal androgen receptor inhibitor, apalutamide, yielded durable PSA responses.
This agent was subsequently further investigated in the double-blind, randomized, phase III SPARTAN trial, which compared apalutamide (240 mg per day) plus ADT to placebo plus ADT in patients with nmCRPC with a PSA doubling time of 10 months or less (N = 1207). Treatment with apalutamide compared to placebo prolonged median metastasis-free survival (primary endpoint) by more than 24 months (40.5 months vs 16.2 months; HR 0.28, P<.001). Improvement in metastasis-free survival with apalutamide was observed across all patient subgroups, including patients with nodal disease. These results were supported by consistent improvement across all evaluable secondary endpoints. Time to metastases was significantly longer in patients treated with apalutamide (40.5 months vs 16.6 months; HR 0.27, P<.001), and apalutamide significantly improved progression-free survival (PFS) compared to placebo (40.5 months vs 14.7 months; HR 0.29, P<.001). Time to first symptomatic progression was also delayed in patients receiving apalutamide (not reached [NR]; HR 0.45, P<.001). There was a trend toward improved overall survival (OS) in patients treated with apalutamide, but these data are not yet mature (NR vs 39.0 months; HR 0.70, P = .07).
The adverse events (AEs) associated with apalutamide were mostly mild and easily managed. Patients treated with apalutamide experienced higher rates of any grade fatigue (30.4% vs 21.1%), rash (23.8% vs 5.5%), falls (15.6% vs 9.0%), hypothyroidism (8.1% vs 2.0%), and fracture (11.7% vs 6.5%) compared to patients treated with placebo. Grade 3/4 AEs occurred in 45.1% of patients treated with apalutamide and 34.2% of patients treated with placebo. A total of 10.6% of patients discontinued apalutamide due to AEs, compared to 7.0% of patients in the placebo group. Of note, patients treated with apalutamide maintained health-related quality of life over time, as did patients who received placebo.
The investigators concluded that apalutamide decreased the risk of either metastasis or death by 72%; significantly prolonged median metastasis-free survival in men with high-risk, nmCRPC; and should be considered as a new standard treatment option for these patients.