FDA Approves Apalutamide for Metastatic Castration-Sensitive Prostate Cancer


The FDA has approved apalutamide (Erleada) for the treatment of patients with metastatic castration-sensitive prostate cancer.1

The approval is based on findings from the phase III TITAN trial (NCT02489318), which showed that apalutamide plus androgen deprivation therapy (ADT) led to a 33% reduction in the risk of death compared with placebo and ADT in this patient population (HR, 0.67; 95% CI, 0.51-0.89; P = .0053).2,3

The supplemental new drug application for apalutamide was reviewed as part of the FDA’s Real-Time Oncology Review program, which is designed to have a more efficient review process to make therapies more quickly available to patients.

"Prostate cancer is more difficult to treat once it spreads, and for patients with castration-sensitive disease, it is clear that androgen deprivation therapy (ADT) alone, is often not enough," principal TITAN investigator Kim Chi, MD, medical oncologist at BC Cancer - Vancouver, stated in a press release. "Results from the TITAN study showed that, regardless of the extent of disease, patients with metastatic castration-sensitive prostate cancer have the potential to benefit from treatment with apalutamide in addition to ADT."

In the international, multicenter, placebo-controlled, double-blind, randomized TITAN study, 1052 patients were enrolled who had metastatic castration-sensitive prostate cancer who were newly diagnosed, regardless of prognostic risk, volume of disease, had an ECOG performance status of 0 or 1, and had prior therapy with docetaxel or localized treatment. Patients were randomized to receive oral apalutamide at 240 mg once daily plus ADT or placebo combined with ADT until disease progression, unacceptable toxicity, or end of treatment. The coprimary endpoints were rPFS and OS; secondary endpoints included time to chemotherapy, time to pain progression, time to chronic opioid use, and time to skeletal-related event.

Patients with small cell, ductal, or neuroendocrine carcinoma of the prostate, brain metastases, lymphatic metastases, visceral metastases, a prior malignancy within 5 years of randomization, a history of seizures, or prior treatment with other next-generation AR inhibitors or CYP17 inhibitors, immunotherapy, or radiopharmaceutical agents were excluded.

Results also showed that at a median follow-up of 22.7 months, the 2-year overall survival (OS) rate was 82.4% in the apalutamide arm versus 73.5% in patients receiving ADT alone (HR, 0.67; 95% CI, 0.51-0.89; P = .005). The median OS was not yet reached in either arm.

Moreover, the addition of apalutamide also reduced the risk of radiographic progression or death by 52%. The median radiographic progression-free survival (rPFS) was not reached in the apalutamide arm versus 22.1 months in the control arm (HR, 0.48; 95% CI, 0.39-0.60; P <.0001). The 2-year rPFS rates were 68.2% versus 47.5%, respectively. The OS and rPFS benefits were observed across patient subgroups.

Key secondary and exploratory endpoints with the addition of apalutamide to ADT were also met. Among these were median time to cytotoxic chemotherapy (HR, 0.39; 95% CI, 0.27-0.56; P<.0001) and median time to PSA progression (HR, 0.26; 95% CI, 0.21-0.32). In the apalutamide arm, 68% of patients had their PSA drop to undetectable levels compared with 29% of patients receiving ADT alone.

The additional of apalutamide to ADT also led to a 34% risk reduction in the median time to second progression-free survival (HR, 0.66; 95% CI, 0.50-0.87)—the time from randomization to either progressive disease on the first subsequent anticancer treatment, or death.

Regarding safety, grade 3/4 adverse events (AEs) occurred in 42.2% of the apalutamide arm versus 40.8% of the control arm. Serious AEs occurred in 19.8% versus 20.3%, respectively. Discontinuations related to AEs occurred in 8% of the apalutamide group compared with 5.3% in the group receiving ADT alone. There were 10 AE-related deaths in the apalutamide arm versus 16 in the placebo arm.

Grade ≥3 AEs of special interest included rash (6.3% in the apalutamide arm vs 0.6% in the ADT-alone arm), fatigue (1.5% vs 1.1%, respectively), fall (0.8% in each arm), fracture (1.3% vs 0.8%), and seizure (0.2% vs 0).

In January 2019, Janssen announced that due to these data from a preplanned analysis, along with a recommendation by an Independent Data Monitoring Committee, the study had been unblinded.4 Based on the positive results favoring apalutamide, the committee recommended that patients on the placebo/ADT arm be allowed to cross over to the apalutamide arm. Patients will continue to be followed for OS and long-term safety as part of the TITAN trial.

"Erleada has the potential to change how patients with prostate cancer are treated, regardless of the extent of the disease or prior docetaxel treatment history, by delaying disease progression and prolonging survival," Margaret Yu, MD, vice president, Prostate Cancer Disease Area Leader, Janssen Research & Development, LLC, stated in the press release. “For patients with prostate cancer as we continue to develop innovative treatments across the disease continuum.”

Apalutamide was approved by the FDA for the treatment of patients with nonmetastatic castration-resistant prostate cancer in February 2018.


JU.S. FDA Approves Supplemental New Drug Application (sNDA) for ERLEADA (apalutamide) for the Treatment of Patientsbwith Metastatic Castration-Sensitive Prostate Cancer (mCSPC). Janssen. Published September 17, 2019. https://prn.to/2kRwT6m. Accessed September 17, 2019.

Chi KN, Agarwal N, Bjartell A, et al. First results from TITAN: A phase III double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT). J Clin Oncol. 2019;37(suppl; abstr 5006).

Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer [published online May 31, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1903307.

Janssen Announces ERLEADA®(apalutamide) Phase 3 TITAN Study Unblinded as Dual Primary Endpoints Achieved in Clinical Program Evaluating Treatment of Patients with Metastatic Castration-Sensitive Prostate Cancer. Janssen. Published January 30, 2019. https://bit.ly/2UuyCL1. Accessed January 30, 2019.

This article originally appeared on OncLive, titled "FDA Approves Apalutamide for Metastatic Castration-Sensitive Prostate Cancer."

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