The phase III ACIS trial met its primary endpoint at 6 months, showing that apalutamide plus abiraterone acetate/prednisone extended radiographic progression-free survival vs abiraterone acetate/prednisone alone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. An updated analysis performed at 4.5 years found that apalutamide plus abiraterone acetate/prednisone continued have a similar reduction in radiographic progression-free survival vs abiraterone acetate/prednisone. However, there was no difference in overall survival between the two treatment groups. These findings were presented by Dana E. Rathkopf, MD, and colleagues at the 2021 Genitourinary Cancers Symposium (Abstract 9).

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 in the combination therapy arm: a median of 22.6 months vs 16.8 months, respectively, for a 31% benefit in risk of progression or death favoring the combination (P < .0001). An updated analysis at a median follow-up of 54.8 months showed a 30% difference favoring the combination arm: a median time to radiographic progression-free survival of 24.4 months for the combination vs 16.6 months for abiraterone acetate/prednisone.

A subgroup analysis suggested that older patients and those with visceral metastasis may have a greater benefit from apalutamide plus abiraterone acetate/prednisone.

Dana E. Rathkopf, MD

“ACIS met its primary endpoint. The combination 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 combination; however, the quality of life was comparable between treatment arms on the FACT-P,” said lead author Dr. Rathkopf, a medical oncologist at Memorial Sloan Kettering Cancer Center.

“Insights from the ACIS study regarding differences in benefit for specific patient subgroups treated with the combination warrant additional evaluation,” she added.

Background

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 abiraterone acetate/prednisone, both approved for the treatment of metastatic castration-resistant prostate cancer, have distinct mechanisms of action on the androgen receptors. The phase III ACIS study sought to compare the benefit of combining these two drugs for the first-line treatment of metastatic castration-resistant prostate cancer.

ACIS enrolled 982 patients with metastatic castration-resistant prostate cancer who had experienced disease progression on androgen-deprivation therapy. Patients had not been treated with prior systemic therapy. Stratification factors were the presence or absence of visceral disease; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and geographic region.

Patients were randomly assigned 1:1 to receive apalutamide plus abiraterone acetate/prednisone (apalutamide at 240 mg daily plus abiraterone at 1,000 mg daily/prednisone at 5 mg twice daily) vs abiraterone acetate/prednisone alone (same dose). The study’s primary endpoint was radiographic progression-free survival; 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, median follow-up was 25.7 months. At that time, the independent data monitoring committee recommended maintaining the study blinding until the planned final analysis of overall survival at a median follow-up of 54.8 months.

Baseline characteristics were comparable between the two treatment arms. The median age was 71 years; a Gleason score of 7 or lower was observed in about 42% of patients, while 58% had Gleason score > 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. About 46% were metastasis-free at the time of diagnosis.

Study Results

At the primary analysis, patients treated with apalutamide plus abiraterone acetate/prednisone had a 31% reduction in death and risk of radiographic progression compared with abiraterone acetate/prednisone, for a 6-month absolute difference favoring the combination. In a prespecified subgroup analysis, the combination of apalutamide plus abiraterone acetate/prednisone was more favorable in patients aged 75 and older and in those with visceral metastases.

At the final overall survival analysis, patients treated with apalutamide plus abiraterone acetate/prednisone had a 30% reduction in death and risk of radiographic progression compared with abiraterone acetate/prednisone, but overall survival was no different between the two treatment arms: a median of 36.2 months for the combination and 33.7 months for abiraterone acetate/prednisone alone.

Prostate-specific antigen (PSA) outcomes at the final analysis favored the combination arm; 79% vs 72.9%, respectively, had a confirmed decline of 50% or more in PSA; 24.6% vs 19.2% had undetectable PSA at any time during treatment.

Prespecified biomarker subgroups favored treatment with the 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 the combination and for abiraterone acetate/prednisone alone. The most common adverse effects in the combination arm were fatigue, hypertension, skin rash, and cardiac disorders. Fractures and osteoporosis of any grade were more common with the combination therapy, with grade 3 and 4 such events being slightly more common in the combination therapy arm.

Despite this, health-related quality of life was comparable between treatment arms according to the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score.  

Disclosures: For full disclosures of the study authors, visit coi.asco.org.