Adding apalutamide (Erleada) to abiraterone acetate (Zytiga) and prednisone did not improve overall survival versus abiraterone/prednisone alone in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC), according to results from the phase 3 ACIS study.1
Janssen Pharmaceutical (Johnson & Johnson), the developer of apalutamide, reported in a press release that it will no longer be pursuing regulatory approval of the novel treatment regimen.
“Safety results from ACIS were consistent with prior studies of Erleada and Zytiga 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, Clinical Development, Solid Tumors, Janssen Research & Development, stated in the press release.
“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,” added Patel.
Overall survival was a secondary end point of the ACIS trial; the final results for the primary end point of radiographic progression-free survival (rPFS) were previously reported at the 2021 Genitourinary Cancers Symposium.2 The results showed that adding apalutamide to abiraterone and prednisone reduced the risk of radiographic progression or death by 30% in patients with chemotherapy-naïve mCRPC.
At a median follow-up of 54.8 months, the median rPFS was 24 months with the addition of apalutamide compared with 16.6 months with placebo plus abiraterone and prednisone (HR, 0.70). The data sustained the rPFS benefit with apalutamide observed at the primary efficacy analysis conducted at a median follow-up of 25.7 months: 22.6 months with apalutamide versus 16.6 months in the control arm (HR, 0.69; P <.0001).
The double-blind phase 3 ACIS study included 982 patients with chemotherapy-naïve mCRPC who received ADT. Baseline characteristics were well balanced between the 2 treatment arms. Overall, the median patient age was 71 years, about 53% of patients had a Gleason score >7, the median PSA level was about 32 ng/mL, and all patients had an ECOG performance status of 0 (68%) or 1 (32%).
Patients were randomized 1:1 to apalutamide (n = 492) or placebo (n = 490) plus abiraterone and prednisone. All patients remained on continuous ADT. Patient randomization occurred between December 10, 2014, and August 30, 2016.
At the final rPFS analysis, 79.5% of patients in the apalutamide/abiraterone arm had a PSA decline ≥50% compared with 72.9% in the control arm (P = .015). Also, 24.6% versus 19.2% of the 2 arms, respectively, had undetectable PSA (<0.2 ng/mL) at any time during treatment (P = .040). However, the improved PSA decline with the apalutamide/abiraterone combo did not translate into a significant benefit in median time to PSA progression at 13.8 months versus 12 months in the control arm (P = .076).
The time to initiation of cytotoxic chemotherapy was 36.1 months versus 34.2 months, respectively (P = .509). The times to chronic opioid use and pain progression were 47 months versus 53.3 months (P = .500) and 21.8 months versus 26.5 months (P = .188), respectively.
Regarding toxicity, no new safety signals were reported compared with previous reported studies of apalutamide. About two-thirds (63.3%) of patients in the apalutamide arm experienced treatment-emergent adverse events (TEAEs), compared with 56.2% of patients in the control group.
Several grade 3/4 TEAEs were more common in the apalutamide/abiraterone combination arm compared with the control arm: hypertension (20.6% vs 12.5%), fatigue (4.7% vs 3.9%), cardiac disorders (9% vs 5.7%), fall (3.3% vs 0.6%), skin rash (4.5 percent vs. 0.4 percent), seizures (0.2% vs 0), and fractures and osteoporosis (4.1% vs 1.4%).
The androgen receptor inhibitor apalutamide is currently approved by the FDA for the treatment of patients with nonmetastatic CRPC and metastatic castration-sensitive prostate cancer. The CYP17 inhibitor abiraterone has FDA-approved indications for use in combination with prednisone in patients with metastatic CRPC and metastatic high-risk castration-sensitive prostate cancer.
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. Published online April 20, 2021. Accessed April 20, 2021. https://bit.ly/3sAuVnG
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-naive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2021;39(suppl 6):9. doi: 10.1200/JCO.2021.39.6_suppl.9