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Apalutamide plus androgen deprivation therapy maintained an overall survival advantage over placebo for a broad population of patients with metastatic castration-sensitive prostate cancer after nearly 4 years of median follow-up.
Apalutamide (Eeleada) plus androgen deprivation therapy (ADT) maintained an overall survival (OS) advantage over placebo for a broad population of patients with metastatic castration-sensitive prostate cancer (mCSPC) after nearly 4 years of median follow-up, according to Kim N. Chi, MD.
Chi, a leading investigator into apalutamide, provided his insights into final analysis data from the phase 3 TITAN trial (NCT02489318) during an OncLive® Rapid Readout program, a video series that features experts delving into key investigations presented at conferences. He is a professor at the University of British Columbia and a medical oncologist and regional medical director of BC Cancer―Vancouver Center, in Canada.
In the final analysis, the addition of the antiandrogen agent apalutamide to ADT reduced the risk for death by 35% (HR, 0.65; 95% CI, 0.53-0.79; P < .0001). After a median follow-up of 44.0 months, the median OS was not reached (NR) in the experimental group compared with 52.2 months with placebo plus ADT (TABLE 11).
During the trial, nearly 40% of patients in the placebo arm crossed over to apalutamide. When these patients were taken into consideration, the apalutamide regimen showed an even greater survival benefit, reducing the risk for death by 48% (HR, 0.52; 95% CI, 0.42-0.64; P < .0001).1
“The treatment effect on overall survival favored apalutamide across all prespecified subgroups, including those with both low- and high-volume disease,” said Chi, who presented the findings during the 2021 Genitourinary Cancers Symposium, which was held virtually in February. “…These results confirm the favorable risk/benefit profile of apalutamide.”
In September 2019, the FDA expanded the indication for apalutamide to include patients with mCSPC based on earlier findings from TITAN.2 The agency previously approved the agent in 2018 for patients with nonmetastatic CRPC.
The approval of apalutamide for patients with mCSPC is part of a recent expansion of therapies for this disease setting, also called metastatic hormone-sensitive prostate cancer.
Starting in 2015, clinical trial evidence has established a role in mCSPC for apalutamide, abiraterone acetate (Zytiga), enzalutamide (Xtandi), and docetaxel. These agents, used in combination with ADT, have been shown to improve survival in patients with mCSPC.3
Apalutamide is an oral nonsteroidal androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR, thereby inhibiting AR nuclear translocation and DNA binding.4 In TITAN, Chi et al hypothesized that directly affecting AR activity with apalutamide in conjunction with ADT would result in a more effective blockade of AR signaling.5
In TITAN, an international, randomized, double-blind trial, investigators enrolled 1052 patients with mCSPC across 260 sites. Eligible patients had adenocarcinoma of the prostate and distant metastatic disease consisting of 1 or more lesions with or without visceral or lymph node involvement. The median age was 68 years and 62.7% of patients had high-volume disease. Approximately 11% of participants had prior docetaxel therapy and approximately 16% had been previously treated for localized prostate cancer including with prostatectomy and radiotherapy. However, they were not receiving ADT at time of disease progression.4
Patients were assigned to apalutamide 240 mg daily (n = 525) or placebo (n = 527). All patients received continuous ADT of either concomitant gonadotropin-releasing hormone therapy or prior bilateral orchiectomy. Treatment continued on 28-day cycles until disease progression or unacceptable toxicity.
In the initial results from TITAN, conducted after a median follow-up of 22.7 months, the OS was 82.4% with apalutamide compared with 73.5% in the placebo group (HR, 0.67; 95% CI, 0.51-0.89; P = .005). However, median OS was not reached in either arm. The 2-year rate of radiographic progression-free survival (rPFS) was 68.2% with apalutamide vs 47.5% with ADT alone, a 52% reduction in the risk for radiographic progression or death (HR, 0.48; 95% CI, 0.39-0.60; P < .0001). The median rPFS was not reached for the apalutamide arm compared with 22.1 months for the placebo plus ADT arm.4
In the final analysis, apalutamide therapy showed improvements over placebo, respectively, for extended time to second PFS on next subsequent therapy (NR vs 44.0 months; HR, 0.62; 95% CI, 0.51-0.75; P < .0001) and delayed time to castration resistance (NR vs 11.4 months; HR, 0.34; 95% CI, 0.29-0.41; P < .0001), defined as time from randomization to first occurrence of radiographic or prostate-specific antigen, or symptomatic skeletal event. There was no difference in health-related quality of life between the treatment groups.
“The benefit with apalutamide was consistent across other end points, and health-related quality of life was maintained with apalutamide,” Chi said. “Treatment was tolerable and there were no new safety signals.”
Only patients who received prior docetaxel did not derive a survival benefit from apalutamide. However, Chi pointed out that those patients represented only 10% of the patient population and there were relatively few adverse events within this group. “A post hoc interaction analysis between treatment and prior use of docetaxel showed no significant interaction,” he added.
The median treatment duration was 39.3 months in the apalutamide arm compared with 20.2 months for the placebo arm. In patients who crossed over, the median treatment duration on apalutamide was 50.4 months.
Chi said the safety profile remained consistent with prior findings despite the longer follow-up (TABLE 21). The most common grade 3 or higher adverse events in the experimental group were skin rash (6.3%), followed by fracture (3.4%), and ischemic heart disease (3.1%).
The apalutamide prescribing information carries a warning about the risk of falls and fractures, with the advice that patients should be evaluated for risk and treated with bone-targeting agents as appropriate.4 However, patients assigned to apalutamide did not experience more falls or fractures than those in the placebo arm.
“Importantly, given the difference in expo-sure between the apalutamide and placebo groups, cumulative incidence of any-grade treatment-emergent falls, fractures, and fatigue were similar between groups,” Chi said. “The cumulative incidence of grade 3/4 treatment-emergent adverse events and serious adverse events was also similar between groups.”