Confirmed clinical benefit of apalutamide in castration-resistant prostate cancer, but no significant survival benefit
Previously presented results of the SPARTAN trial demonstrated that apalutamide in combination with continued androgen deprivation therapy significantly prolongs the metastasis-free survival in patients with non-metastatic castration-resistant prostate cancer. Updated results of this trial further solidify this finding and also showed a significant delay in the time to first chemotherapy and in the time from randomization to disease progression on the first subsequent line of therapy. While apalutamide was found to be associated with a 25% reduction in the risk of death compared to placebo, this difference did not reach statistical significance. Longer follow-up is needed to elucidate whether this strong trend for an overall survival benefit will ultimately result in a significant survival benefit with apalutamide in this setting.
In the phase III SPARTAN trial, 1,207 patients with non-metastatic castration-resistant prostate cancer (nmCRPC) were randomly assigned (2:1) to receive the potent oral next-generation androgen receptor inhibitor apalutamide (240 mg QD) or placebo. All patients in the trial continued to be treated with androgen deprivation therapy (ADT). In order to be eligible for the study, patients had to have a PSA doubling time of 10 months or less. In the primary analysis of this trial, with a median follow-up of 20.3 months, apalutamide was found to be associated with a significantly longer metastasis-free survival (MFS) compared to placebo (median MFS: 40.5 vs 16.2 months; HR [95% CI]: 0.28 [0.23-0.35]; p<0.0001). In addition, also the secondary endpoint of time to symptomatic progression was significantly longer with apalutamide compared to placebo (HR [95% CI]: 0.45 [0.32-0.63]; p<0.0001). During ESMO updated results of SPARTAN were presented with a median follow-up of 41 months. At the time of this prespecified analysis, 67% of the required OS events had occurred and the required p-value for statistical significance at this point was 0.0121.
Apalutamide was associated with a 25% reduction in the risk of death compared to placebo (HR [95% CI]: 0.75 [0.59-0.96]; p=0.0197). At four years, this corresponds to an OS rate of 72.1% in the apalutamide arm as compared to 64.7% among placebo-treated patients. Unfortunately, this p-value of 0.0197 just failed to meet the preset criterion for statistical significance (<0.0121). Of note, the treatment effect of apalutamide was consistent among all investigated subgroups, including age, geographical region, PSA doubling time and baseline ECOG performance status.
In total, 197 patients had initiated cytotoxic chemotherapy (115 and 82 in the apalutamide and placebo arm, respectively). Interestingly, the time to the initiation of chemotherapy was significantly longer for patients who received apalutamide compared to placebo (HR [95% CI]: 0.60 [0.45-0.80]). Also with respect to the time to progression on the first subsequent therapy (PFS2) a significant difference was seen with apalutamide versus placebo. Overall, 69% of the placebo-treated patients and 40% of the apalutamide-treated patients received a subsequent life-prolonging therapy (most frequently abiraterone acetate). While the median PFS2 was reported at 43.8 months for placebo-treated patient, this was prolonged to 55.6 months with apalutamide (HR [95% CI]: 0.55 [0.45-0.68]; p<0.0001). In this updated analysis, the safety profile of apalutamide remained consistent with previous reports.
In summary, apalutamide was associated with a 25% reduction in the risk of death compared to placebo in ADT-treated patients with nmCRPC and this OS benefit was consistent among all investigated subgroups. At the time of this analysis this difference in OS did not yet reach statistical significance. Nevertheless, the presenters concluded that the significant improvements in terms of MFS, time to chemotherapy initiation and PFS2 in combination with this strong trend for an OS benefit further support apalutamide as a standard of care option for patients with high-risk nmCRPC. Final OS results of this trial are awaited.
Smith M, et al. Apalutamide (APA) and overall survival (OS) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): Updated results from the phase III SPARTAN study. Presented at ESMO 2019; Abstract 843O.