ASCO GU 2021: Final Results of ACIS Support Addition of Apalutamide to Abiraterone-Prednisone for Advanced Prostate Cancer
The study also identified clinical features and biomarkers that may help identify those most likely to benefit
February 11, 2021—Adding the androgen receptor inhibitor apalutamide to abiraterone-prednisone therapy in patients with treatment-naïve advanced prostate cancer improves outcomes, particularly among older patients, according to the final analysis of the ACIS trial. The findings were presented at the 2021 virtual meeting of the American Society of Clinical Oncology Genitourinary Cancers Symposium, which took place from February 11 to 13.
“Metastatic castration-resistant prostate cancer is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said lead author Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center in New York, during her presentation of the data. “Apalutamide, an androgen receptor inhibitor, and separately, abiraterone acetate plus prednisone, which suppresses the androgen ligand, are approved prostate cancer therapies. The objective of the ACIS study was to assess whether inhibition with the combination of apalutamide and abiraterone acetate plus prednisone … would provide a better clinical benefit than [abiraterone plus prednisone] alone.”
For the phase III ACIS trial, 982 chemotherapy-naïve patients with metastatic castration-resistant prostate cancer receiving androgen deprivation therapy but no other life-prolonging treatment were enrolled between December 2014 and August 2016. The patients were randomized 1:1 to receive apalutamide 240 mg once daily, abiraterone 1000 mg once daily, and prednisone 5 mg twice daily or placebo plus abiraterone and prednisone. The patients were stratified by presence or absence of visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, and geographic region. Treatment continued in 28-day cycles until disease progression, withdrawal of consent, or occurrence of unacceptable toxicity.
The primary endpoint of the trial was radiographic progression-free survival (PFS) by investigator assessment, defined from the randomization date to the radiographic progression date or death. Secondary and additional endpoints included prostate-specific antigen (PSA) response, overall survival (OS), safety, time to PSA progression, chronic opioid use, initiation of cytotoxic chemotherapy, and pain progression.
At the final analysis for radiographic PFS in March 2018, which occurred at a median of 25.7 months of follow-up, the median radiographic PFS was extended by about 6 months with apalutamide therapy, from 16.6 months in the placebo group to 22.6 months in the apalutamide-treated group (hazard ratio 0.69, 95% confidence interval 0.58–0.83, P < .0001). At this point, continued blinding of the study was recommended by an independent data monitoring committee.
The follow-up analysis presented at ASCO-GU involved outcomes after a median of 54.8 months. At this time, the benefits of adding apalutamide continued to be evident, with a radiographic PFS of 24.0 months with the addition of this agent and 16.6 months without (hazard ratio 0.70, 95% confidence interval 0.60–0.83). The greatest benefits were observed in patients ≥ 75 years of age (hazard ratio 0.54, 95% confidence interval 0.40–0.73) and were also present among patients with visceral metastases (hazard ratio 0.69, 95% confidence interval 0.45–1.05). Superior outcomes were observed among patients who had tumors with molecular signatures indicating hormone sensitivity, based on luminal histology and presence of androgen receptor responsive genes.
There were no differences between the two groups at 54.8 months with respect to OS, although it was numerically greater with apalutamide, at 36.2 versus 33.7 months. The OS was significantly improved with apalutamide among patients aged 75 and older, however (hazard ratio 0.75, 95% confidence interval 0.59–0.96). There were also no differences between the two groups with respect to prespecified secondary endpoints.
Presence of undetectable PSA at any point during treatment (24.6% vs 19.2%, P = .04) and confirmed decline in PSA ≥ 50% (79.5% vs 72.9%, P = .015) both favored apalutamide-containing therapy. “However,” said Dr. Rathkopf, “this PSA decline favoring the combination arm translated into only a marginal delay in time to PSA progression” (13.8 vs 12.0 months, P = .076).
The safety profile of the treatment was consistent with previous studies, and no new safety concerns arose. The rate of grade 3/4 treatment-emergent adverse events was 63.3% with apalutamide and 56.2% without. There were treatment-emergent adverse events associated with death among 3.5% of patients in the apalutamide group and 7.6% in the placebo group. Grade 3/4 events of special interest included fatigue (4.7% vs 3.9%), hypertension (20.6% vs 12.5%), skin rash (4.5% vs 0.4%), cardiac disorders (9.0% vs 5.7%), and osteoporotic fracture (4.1% vs 1.4%). Health-related quality of life was similar for both arms.
“ACIS met its primary endpoint,” concluded Dr. Rathkopf. “Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone in metastatic castration-resistant prostate cancer.”
The ACIS trial received funding from Janssen Research and Development.
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