Regulatory Submissions for Apalutamide Combo in Metastatic CRPC Will Not Be Pursued


Regulatory submissions for the combination of apalutamide plus abiraterone acetate and prednisone in the treatment of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer will not be pursued.

Kiran Patel, MD

Kiran Patel, MD

Regulatory submissions for the combination of apalutamide (Erleada) plus abiraterone acetate (Zytiga) and prednisone in the treatment of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC) will not be pursued, according to an announcement from The Janssen Pharmaceutical Companies of Johnson & Johnson.1

The triplet, which was under examination in the phase 3 ACIS study (NCT02257736), was shown to reduce the risk of radiographic progression or death by 30% in patients with chemotherapy-naïve metastatic CRPC who were receiving androgen deprivation therapy (ADT).2

At a median follow-up of 54.8 months, the median radiographic progression-free survival (rPFS) was 24 months with the apalutamide combination vs 16.6 months with placebo plus abiraterone/prednisone (HR, 0.70).

The findings demonstrated sustained rPFS benefit with the apalutamide regimen that had been observed at the time of the primary efficacy analysis which was done at a median follow-up of 25.7 months. At that time point, the median rPFS in the investigative and control arms was 22.6 months and 16.6 months, respectively (HR, 0.69; P <.0001). Moreover, the rPFS benefit achieved with the triplet was sustained across prespecified subgroups.

However, the addition of apalutamide to abiraterone/prednisone did not result in an overall survival (OS) benefit. At final analysis, the median OS was 36.2 months with the apalutamide regimen vs 33.7 months with abiraterone/prednisone alone (HR, 0.95; 95% CI, 0.81-1.11; P = .498).

“Safety results from ACIS were consistent with prior studies of [apalutamide] and [abiraterone] plus prednisone, with no new safety signals observed. The study also generated valuable scientific outcomes and insights in subgroups of patients with luminal type in PAM50 test and tumors with average or high androgen receptor activity (molecular signatures of hormone sensitivity), which warrant further investigation,” Kiran Patel, MD, vice president of clinical development, solid tumors, at Janssen Research & Development, LLC, stated in the press release.

A total of 982 patients were enrolled to the placebo-controlled, double-blind, phase 3 ACIS trial. To be eligible for enrollment, patients needed to have mCRPC that had progressed on ADT, an ECOG performance status of 0 or 1, and a pain score of 3 or less. Patients could not have previously received chemotherapy or androgen synthesis inhibition for castration-resistant disease.

Study participants were randomized 1:1 to receive either apalutamide at a daily dose of 240 mg plus abiraterone at a once-daily dose of 1000 mg and prednisone at a twice-daily dose of 5 mg (n = 492) or abiraterone and prednisone alone at the same dosing/schedule (n = 490). Treatment was given until progressive disease, withdrawn consent, or intolerable toxicity. Patients were stratified based on visceral metastases (presence vs absence), performance status (0 or 1), and geographic region (North America, Europe/United Kingdom or rest of the world).

The primary end point of the trial was rPFS per investigator assessment and key secondary end points comprised OS, time to initiation of cytotoxic chemotherapy, time to pain progression, and time to chronic opioid use. Other exploratory end points included time to clinical progression, time to first subsequent anticancer treatment, time to second PFS, decline in prostate-specific antigen (PSA), time to PSA progression, patient-reported outcomes, and safety.

The median age of patients at baseline was 71.0 years and 52.9% of patients had a Gleason score of greater than 7 at the time of diagnosis. Moreover, the majority of patients had an ECOG performance status of 0 and the median baseline PSA across the arms was 31.8 ng/mL. Most patients, or 85.1% had disease in the bone at baseline.

Additional results presented during the 2021 Genitourinary Cancers Symposium indicated that results from other prespecified secondary outcomes such as initiation of cytotoxic chemotherapy (P = .498), chronic opioid use (P = .509), and pain progression (P = .500) were also similar between the 2 treatment arms.

At the time of the final analysis, 79.5% of patients in the investigative arm vs 72.9% of those in the control arm experienced a confirmed decline of 50% or greater in PSA level (P = .015). Moreover, 24.6% and 19.2% of those who received the triplet and the doublet, respectively, had undetectable PSA at any time during treatment (P = .040). The median time to PSA progression was 13.8 months with the apalutamide regimen vs 12.0 months with abiraterone/prednisone alone (HR, 0.87; 95% CI, 0.74-1.02; P = .076).

Regarding safety, 62.5% of those on the investigative arm and 64.8% of those on the control arm discontinued treatment and were treated with first subsequent life-prolonging therapy. The safety of the triplet was found to be consistent with prior data on the agents. Moreover, health-related quality of life was found to be comparable between the 2 treatment arms.

“These data will be important in informing future programs in our pipeline, as we look to build upon our leadership and commitment in bringing transformational therapies to patients diagnosed with prostate cancer,” Patel added in the release.


  1. Janssen provides update on phase 3 ACIS study in patients with metastatic castration-resistant prostate cancer treated with ERLEADA (apalutamide) and ZYTIGA (abiraterone acetate) plus prednisone combination. News release. April 19, 2021. Accessed April 19, 2021.
  2. Rathkopf DE, Efstathiou E, Attard G, et al. Final results from ACIS, a randomized, placebo (PBO)-controlled double-blind phase 3 study of apalutamide (APA) and abiraterone acetate plus prednisone (AAP) versus AAP in patients (pts) with chemo-naïve metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2021;39(suppl 6):9. doi:10.1200/JCO.2021.39.6_suppl.9
Related Videos
Expert on prostate cancer
Kevin Kayvan Zarrabi, MD, MS, FACP
Clara Hwang, MD
Clara Hwang, MD
Joshi Alumkal, MD
Clara Hwang, MD
Clara Hwang, MD
Alexandra Sokolova, MD
Expert on prostate cancer
Experts on prostate cancer
Related Content