Apalutamide Submitted to FDA for Treatment of Metastatic Castration-Sensitive Prostate Cancer

Apalutamide has been submitted for FDA approval for the treatment of patients with metastatic castration-sensitive prostate cancer.

Craig Tendler, MD

Apalutamide (Erleada) has been submitted for FDA approval for the treatment of patients with metastatic castration-sensitive prostate cancer, according to Janssen, the manufacturer of the next-generation androgen receptor inhibitor.1

In findings from the phase III TITAN trial (NCT02489318), on which the supplemental new drug application (sNDA) was based, apalutamide plus androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) compared with placebo and ADT in this patient population. Full findings from the study will be presented at the 2019 ASCO Annual Meeting.

The sNDA is being reviewed under the FDA’s Real-Time Oncology Review program. The program is designed to have a more efficient review process to make therapies available to patients more quickly. Selection into this program does not guarantee or influence approvability of the application, Janssen stated in a press release.

“This submission marks an important step in providing a potential treatment option for patients with metastatic castration-sensitive prostate cancer, regardless of prior treatment or the extent of their disease,” Craig Tendler, MD, vice president, Oncology Clinical Development and Medical Affairs, Janssen Research & Development, LLC, said in a press release. “We look forward to closely collaborating with the FDA through the efficient Real-Time Oncology Review pilot program with the goal of bringing Erleada to an earlier population of patients with metastatic prostate cancer as soon as possible.”

Patients with metastatic castration-sensitive prostate cancer tend to have a poor prognosis, Janssen noted in the press release. The median OS is less than 5 years, which underscores the need for new therapeutic options.

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.

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.2Based 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.

Apalutamide is currently indicated for the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC). The February 2018 approval was based on results from the phase III SPARTAN trial, which demonstrated that apalutamide reduced the risk of metastasis or death by 72% in patients with nonmetastatic CRPC.3In SPARTAN, 1207 patients were randomized 2:1 to receive 240 mg of apalutamide daily (n = 806) or placebo (n = 401). The average baseline prostate-specific antigen doubling time was <5 months in both arms. Those who developed metastases were allowed to receive abiraterone acetate (Zytiga) plus prednisone.

The primary endpoint of SPARTAN was metastasis-free survival; secondary endpoints included time to metastasis, progression-free survival, time to symptomatic progression, and OS. Investigators also looked at time between randomization to first treatment for metastatic CRPC and subsequent progression (PFS2) for patients who developed metastases.

Findings showed that the median MFS was 40.5 months with apalutamide compared with 16.2 months with placebo (HR, 0.28; 95% CI, 0.23-0.35;P<.0001). Regarding safety, adverse events led to discontinuation in 10.7% and 6.3% of the apalutamide and control arms, respectively. There was no reduction in mean baseline health-related quality-of-life scores in either arm as the trial progressed, nor was there a difference over time in the scores between the groups. PFS2 was also longer for patients who were initially randomized to apalutamide.


  1. Janssen Submits Application to U.S. FDA Seeking Approval of ERLEADA&reg;(apalutamide) for Patients with Metastatic Castration-Sensitive Prostate Cancer. Janssen. Published April 29, 2019. https://bit.ly/2V4efcv. Accessed April 29, 2019.
  2. Janssen Announces ERLEADA&reg;(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.
  3. Small EJ, Saad F, Chowdhury S et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).J Clin Oncol. 2018;36(suppl 6s; abstract 161).