Background
The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC.
Methods
ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.
Findings
982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plus abiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5–58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7–27·5) versus 16·6 months (13·9–19·3; HR 0·70, 95% CI 0·60–0·83; p<0·0001). The most common grade 3–4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone–prednisone and 49 [10%] of 489 receiving abiraterone–prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone–prednisone and 181 (37%) patients receiving abiraterone–prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone–prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone–prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death).
Interpretation
Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC.
Funding
Janssen Research & Development.
By Dr. Guillaume Ploussard
In this Article of the Month, the authors reported the outcome analysis of the phase-III ACIS trial, comparing abiraterone acetate with or without apalutamide in addition to androgen blockage in metastatic, castration-resistant prostate cancer (mCRPC) patients. Until now, no combination trial has shown any survival advantage at the mCRPC stage. This trial was conducted in the second-line setting.
The primary endpoint of the ACIS trial was a radiographic progression-free survival. Overall, 982 mCRPC, first-line, chemo-naive patients were included in this combination trial between 2014 and 2016. Secondary endpoints were overall survival, time to initiation of cytotoxic chemotherapy, time to chronic opioid use, and time to pain progression. Treatment with apalutamide plus abiraterone led to a significant improvement in radiographic progression-free survival compared with abiraterone (plus placebo) at the time of primary analysis (HR 0.69, 95% CI 0.58–0.83; p<0.0001). At the time of final analysis (4.5 years of follow-up), the significant radiographic progression-free survival benefit persisted (HR 0.70; p<0.0001). Thus, despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone/prednisone improved radiographic progression-free survival. The concordance between the central and investigator review of the radiographic progressive disease was 75% with a high positive correlation coefficient in both treatments.
No overall survival benefit was achieved by the combination. The median overall survival surpassed three years with apalutamide plus abiraterone (36.2 versus 33.7 months). At progression, about two-thirds of the patients who had discontinued treatment received subsequent life-prolonging therapy.
Moreover, none of the other secondary endpoints (time to initiation of cytotoxic chemotherapy, time to chronic opioid use, and time to pain progression) reached significance. Analyses of prespecified biomarker subgroups based on molecular signatures (PAM50-luminal and androgen receptor signalling activity) did not find any significant correlation with radiographic progression-free survival. Overall incidence of adverse events was similar between groups. Serious adverse events occurred in 37% of the patients receiving apalutamide plus abiraterone versus 40% of the patients receiving placebo plus abiraterone. Grade 3-4 adverse events were reported in 60% of the patients receiving apalutamide plus abiraterone versus 51% of the patients receiving placebo plus abiraterone. The most commonly adverse event was hypertension (10% -17%). Cardiac disorders occurred with similar frequency in both groups (19%) leading to the 1% of deaths in both groups. Globally, safety was consistent with the previously reported tolerability profiles. Quality-of-life maintenance was equivalent in both arms.
This trial is the first combo phase-III study in castration-resistant prostate cancer that has met its primary endpoint. Nevertheless, no benefit was observed in terms of overall survival. Such a combination won’t probably lead to changes in current guideline treatment recommendations. However, subgroup analyses may help identify patients that would be more likely to benefit. A positive signal was seen in patients aged 75 years and older. In this specific population, the initial combination of two active drugs could be interesting to consider for those who may be unfit to receive subsequent therapy sequences. Future trials are awaited to better define combinations and sequencing at the mCRPC stage in the era of the use of new hormonal agents in this stage.