The next-generation androgen receptor apalutamide, in combination with androgen deprivation therapy, demonstrated a 25% reduction in the risk of death compared with placebo/ADT in patients with nonmetastatic castration-resistant prostate cancer in the phase III SPARTAN trial.
Matthew R. Smith, MD, PhD
The next-generation androgen receptor (AR), apalutamide (Erleada), in combination with androgen deprivation therapy (ADT) demonstrated a 25% reduction in the risk of death compared with placebo/ADT in patients with nonmetastatic castration-resistant prostate cancer (CRPC), according to updated findings of the phase III SPARTAN trial that were presented at the 2019 ESMO Congress.1,2
At a median 41 months of follow-up, results showed that the median overall survival (OS) was not reached in either arm, favoring apalutamide (HR, 0.75; 95% CI, 0.59-0.96; P = .0197). However, due to a prespecified P value boundary of .0121, these data were not found to be statistically significant.
"The P value was .0197; although close, this value was higher than the prespecified O'Brien-Fleming boundary of .0121. Accordingly, the study follow-up will continue per protocol and the final analysis will occur after 427 deaths," lead study author Matthew R. Smith, MD, PhD, director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center, stated in a presentation during the meeting. “Collectively, these results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic castration-resistant prostate cancer.” The FDA approved apalutamide in this setting in February 2018; the approval was based on metastasis-free survival (MFS) data from SPARTAN, which was the primary endpoint. These data showed that apalutamide reduced the risk of metastasis or death by 72% in patients with nonmetastatic CRPC. The median metastasis-free survival (MFS) was 40.5 months in the apalutamide arm versus 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; P <.0001).3
In the international SPARTAN study, researchers evaluated the safety and efficacy of apalutamide versus placebo in 1207 patients with nonmetastatic CRPC and a rapidly rising prostate-specific antigen (PSA) level, despite receiving continuous ADT. Nonmetastatic status was determined by a negative bone scan, as well as a negative CT of the pelvis, abdomen, chest, and brain. Patients were required to have a PSA doubling time of (PSADT) ≤10 months.
Patients were randomized 2:1 to receive 240 mg of apalutamide daily with ADT (n = 806) or placebo with ADT (n = 401). The average baseline PSADT was <5 months in both arms. Those who developed metastases were permitted to receive abiraterone acetate (Zytiga) plus prednisone. Stratification factors also included PSADT ≥6 months or ≤6 months, use of bone-sparing agents, and N0/N1 stage disease.
The primary endpoint was MFS; secondary endpoints included time to metastasis, progression-free survival (PFS), time to symptomatic progression, and OS. For patients who developed metastases, the researchers also evaluated the time between randomization to first treatment for metastatic CRPC and subsequent progression (PFS2).
At the 20.3-month median follow-up, 61% of the apalutamide arm remained on treatment compared with 30% of the placebo group. Based on the preliminary data, an independent data monitoring committee recommended unblinding the trial and allowing patients on the placebo arm to cross over and receive open-label apalutamide (19%, n = 76), Smith said.
Additionally, at this first analysis, apalutamide was found to improve the time to symptomatic progression compared with placebo (HR, 0.45; 95% CI, 0.32-0.63; P <.0001). The first interim OS analysis (24% of events) revealed a trend favoring apalutamide, but data were immature.
At the 2019 ESMO Congress, the updated analysis included data on OS, as well as the effects of apalutamide on time to chemotherapy, PFS2, and safety.
OS was assessed using a preplanned group sequential testing procedure with an O’Brien-Fleming—type alpha spending function. The second interim OS analysis was conducted following 285 OS events, which comprise 67% of the required final events, with a P value boundary of .0121 for statistical significance. The study follow-up will continue per protocol, and the final OS analysis will occur after 427 events (100%), with a P value boundary of ~.047, explained Smith.
Additional results showed that the 4-year OS rates for the apalutamide and placebo arms were 72.1% and 64.7%, respectively.
The apalutamide effect on OS was observed across patient subgroups, especially in those <65 years (HR, 0.33; 95% CI, 0.14-0.74), no prior radical prostatectomy or local radiation (HR, 0.82; 95% CI, 0.60-1.11), N1 stage disease (HR, 0.52; 0.29-0.94), prior bone-sparing therapy (HR, 0.55; 95% CI, 0.27-1.11), and PSADT >6 months (HR, 0.57; 95% CI, 0.34-0.95). The OS benefit was also seen with apalutamide, despite patient crossover from the placebo arm.
Of those who initiated cytotoxic chemotherapy (n = 197), 14% (n = 115) of patients were on apalutamide and 20% (n = 401) were on placebo. The time to initiation of chemotherapy was not reached in either arm (HR, 0.60; 95% CI, 0.45-0.80). “Per protocol sequential testing, time to initiation of chemotherapy was not formally testing for statistical significance since the OS analysis was not significant,” Smith said. “None the less, it appears that apalutamide is associated with a delay in the time to initiation of chemotherapy.”
Moreover, apalutamide was also found to significantly extend PFS2 compared with placebo, with a median PFS2 of 55.5 months and 43.8 months, respectively (HR, 0.55; 95% CI, 0.45-0.68; P <.0001). Sixty-nine percent of those on the placebo arm and 40% of patients on apalutamide received subsequent therapy, which mainly consisted of abiraterone acetate plus prednisone.
Regarding safety, apalutamide’s profile was found to be consistent with prior reports. The median duration of treatment was 31.4 months with the AR inhibitor and 11.5 months with placebo. AEs were reported in 97.3% and 93.7% of apalutamide- and placebo-treated patients, respectively. Grade 3/4 AEs were reported in 53.1% of patients on the apalutamide arm and 36.7% of those on placebo, and serious AEs occurred in 33.5% and 24.9%, respectively. The treatment discontinuation rate was nearly doubled with apalutamide (13.6%) compared with placebo (7.3%). AEs that led to death occurred in 2.1% and 0.5% of patients on apalutamide and placebo, respectively.
Discontinuation rates due to disease progression were 34% in the apalutamide group compared with 74% in the placebo group, Smith explained.
Karim Fizazi, MD, PhD, commented on the OS data as an invited discussant following Smith’s presentation.
“It is true when you’re looking at the hazard ratio, it is 0.5, but as very honestly announced by Dr. Matthew Smith, it is a very nonsignificant difference at this point. The P value is about .02 at the moment, and the boundary to claim [OS significance] is .0121. At the moment, we cannot say that apalutamide prolongs survival in this setting. [With PFS2], there is a more meaningful difference we are seeing; this is utterly important because abiraterone was provided as a potential salvage treatment in both arms. In other words, it is comparing deferred AR-targeting, at least in some patients, and at the same time, it is making a difference in [PFS2].”
In September 2019, the FDA granted a second approval to apalutamide for the treatment of patients with metastatic castration-sensitive prostate cancer.