The phase III ACIS trial met its primary endpoint at 6 months showing that apalutamide plus abiraterone acetate/prednisone (AAP) extended radiographic progression-free survival vs abiraterone acetate/prednisone alone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.1 An updated analysis performed at 4.5 years found that AAP continued to result in a similar reduction in radiographic-free survival vs abiraterone acetate/prednisone alone. However, there was no difference in overall survival between patients who received AAP vs abiraterone acetate/prednisone. All patients were on background androgen-deprivation therapy at baseline.
For the primary efficacy analysis at 6 months, median radiographic progression-free survival was extended by an absolute difference of 6 months with the triplet combination therapy: median of 22.6 months vs 16.8 months, respectively, for a 31% benefit in risk of disease progression or death favoring the triplet (P < .0001). An updated analysis at a median follow-up of 54.8 months showed a 30% difference favoring AAP, with a median time to radiographic progression-free survival of 24.4 months with the triplet vs 16.6 months with abiraterone acetate/prednisone alone. A subgroup analysis suggested that older patients and those with visceral metastasis may reap a greater benefit from AAP.
“Insights from the ACIS study regarding differences in benefit for specific patient subgroups treated with the combination [AAP] warrant additional evaluation.”— Dana Rathkopf, MD
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“ACIS met its primary endpoint. The [triplet] combination arm extended radiographic progression-free survival by 6 months in the primary per protocol analysis and by 7.4 months in the updated final analysis [P < .0001]. This benefit was observed vs an active comparator. Secondary endpoints were similar between the two arms, including overall survival. No new safety signals were observed. Slightly higher rates of treatment-emergent adverse events were observed with the [triplet] combination; however, the quality of life was comparable between treatment arms on the FACT-P,” said lead author Dana Rathkopf, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York. “Insights from the ACIS study regarding differences in benefit for specific patient subgroups treated with the [triplet] combination warrant additional evaluation.”
Metastatic castration-resistant prostate cancer is partly driven by activated androgen receptors, but the overall prostate cancer population is heterogeneous in terms of androgen receptor resistance and sensitivity.
Apalutamide and AAP are both approved for the treatment of metastatic castration-resistant prostate cancer and have distinct mechanisms of action on the androgen receptors. The phase III ACIS study sought to compare the benefit of combining these treatments in the first-line setting of this patient population.
ACIS enrolled 982 patients with metastatic castration-resistant prostate cancer progressing on androgen-deprivation therapy. Patients had not been treated with prior systemic therapy for castration-resistant prostate cancer. Stratification factors were the presence or absence of visceral disease; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and geographic region.
They were randomly assigned 1:1 to receive AAP (apalutamide at 240 mg/d plus abiraterone at 1,000 mg/d and 5 mg of prednisone twice daily) vs abiraterone acetate/prednisone (same dose). The primary endpoint was radiographic progression-free survival; the secondary endpoints included overall survival, time to initiation of cytotoxic chemotherapy, time to pain progression, and time to chronic opioid use.
At the time of the primary analysis, the median follow-up was 25.7 months. At that time, the independent data monitoring committee recommended maintaining the study blind until the planned final analysis of overall survival, at median follow-up of 54.8 months.
Baseline characteristics were comparable between the two treatment arms. The median age of patients was 71 years; Gleason score of 7 or lower was observed in about 42% of patients, whereas 58% had a Gleason score higher than 7; 68% had an ECOG performance score of 0, and 32% had an ECOG performance score of 1. About 85% had bone metastases; 48% had lymph node metastases; about 13% had soft--tissue metastases; and about 15% had visceral metastases. Approximately 46% were free of metastasis at the time of diagnosis.
At the primary analysis, patients treated with AAP had a 31% reduction in death and risk of radiographic disease progression compared with abiraterone acetate/prednisone, for a 6-month absolute difference favoring the combination. In a prespecified subgroup analysis, AAP yielded more favorable results for patients aged 75 and older and for those with visceral metastases.
At the final overall survival analysis, AAP resulted in a 30% reduction in death and risk of radiographic disease progression compared with abiraterone acetate/prednisone. However, there was no difference between the two treatment arms in terms of overall survival: median of 36.2 months for the triplet and 33.7 months for abiraterone acetate/prednisone alone.
At the final analysis, prostate-specific antigen (PSA) outcomes favored the triplet combination arm; 79% and 72.9%, respectively, had a confirmed decline of 50% or more in PSA levels; 24.6% and 19.2%, respectively, had undetectable PSA at any time during treatment.
Prespecified biomarker subgroups favored treatment with the triplet combination for patients with tumors that had molecular signatures for hormone sensitivity (ie, luminal histology and androgen receptor–responsive genes).
No new safety signals were reported for either treatment arm. The most common adverse effects with AAP were fatigue, hypertension, skin rash, and cardiac disorders. Fractures and osteoporosis of any grade were more common with the triplet combination therapy, with the rates of grade 3 and 4 events slightly more common with AAP.
Despite these findings, health-related quality of life was comparable between treatment arms, according to the Functional Assessment of Cancer Therapy–Prostate (FACT-P) total score.
DISCLOSURE: Dr. Rathkopf has served as a consultant or advisor to AstraZeneca, Bayer, Genentech, Janssen, and Myovant Sciences and has received institutional research funding from AstraZeneca, Bayer, Celgene, Ferring, Genentech/Roche, Janssen Oncology, Medivation, Millennium, Novartis, Phosplatin Therapeutics, Taiho Pharmaceutical, Takeda, and TRACON Pharmaceuticals.
1. Rathkopf DE, Efstathiou E, Attard G, et al: Final results of ACIS, a randomized, placebo-controlled double-blind phase 3 study of apalutamide and abiraterone acetate plus prednisone (AAP) versus AAP in patients with chemo-naive metastatic castration-resistant prostate cancer. 2021 Genitourinary Cancers Symposium. Abstract 9. Presented February 11, 2021.
Joshi J. Alumkal, MD
Invited discussant of the ACIS study, Joshi J. Alumkal, MD, leader of the Genitourinary Medical Oncology Section at the University of Michigan Rogel Cancer Center, noted that the toxicities were slightly higher with apalutamide plus abiraterone acetate/prednisone,...