In the phase II ProCAID study reported in the Journal of Clinical Oncology, Crabb et al found that the addition of the pan-AKT inhibitor capivasertib to docetaxel and prednisolone did not significantly improve progression-free survival in patients with metastatic castration-resistant prostate cancer, the trial’s primary endpoint. However, a significant improvement in overall survival was observed, although the investigators noted this would need prospective validation in future studies.
The investigator-initiated, multicenter, double-blind trial included 150 patients screened between September 2015 and January 2019. They were randomly assigned to receive up to 10 21-day cycles of docetaxel at 75 mg/m2 on day 1 and prednisolone at 5 mg twice daily on days 1–21, and either oral capivasertib at 320 mg twice daily for 4 days on/3 days off from day 2 in each cycle (n = 75) or placebo (n = 75) until disease progression.
The primary endpoint was composite progression-free survival including any of prostate-specific antigen, soft tissue, bone metastases, or unequivocal clinical progression, start of new systemic therapy, or death. Outcomes were analyzed in the intention-to-treat population.
Composite Progression-Free Survival
The median follow-up was 23.7 months. Median composite progression-free survival was 7.03 months (95% confidence interval [CI] = 6.28–8.25 months) in the capivasertib group vs 6.70 months (95% CI = 5.52–7.36 months) in the placebo group (hazard ratio [HR] = 0.92, 80% CI = 0.73–1.16, P = .32). Rates at 6 months were 62% vs 56%.
Analysis among 136 patients with available data on biomarkers of PI3K/AKT/PTEN pathway activation showed no significant differences among 44 biomarker-positive patients (median = 7.75 vs 7.98 months, HR = 1.17, 95% CI = 0.61–2.23) or 92 biomarker-negative patients (median = 7.03 vs 6.34, HR = 0.89, 95% CI = 0.57–1.37).
Median overall survival was 31.15 months (95% CI = 20.07 months–not reached) in the capivasertib group vs 20.27 months (95% CI = 17.51–24.18 months) in the placebo group (HR = 0.54, 95% CI = 0.34–0.88, P = .01), with 24-month rates of 56% vs 39%. Results were similar in the biomarker-positive (median = 26.87 vs 20.27 months, HR = 0.62, 95% CI = 0.26–1.47) and biomarker-negative subgroups (median = 32.43 vs 20.30 months, HR = 0.54, 95% CI = 0.30–0.99).
Grade ≥ 3 adverse events occurred in 62% of patients in each group, with the most common in the capivasertib group being neutropenia (26% vs 19% in the placebo group), febrile neutropenia (15% vs 7%), and rash (9% vs 1%). The most common adverse events of any grade considered related to capivasertib were diarrhea, fatigue, nausea, and rash. Adverse events led to discontinuation of treatment in 23% vs 11% of patients.
The investigators concluded, “The addition of capivasertib to chemotherapy did not extend composite progression-free survival in metastatic castration-resistant prostate cancer irrespective of PI3K/AKT/PTEN pathway activation status. The observed overall survival result (a secondary endpoint) will require prospective validation in future studies to address potential for bias.”
Simon J. Crabb, PhD, of Southampton Clinical Trials Unit, Centre for Cancer Immunology, Southampton General Hospital, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Cancer Research UK and AstraZeneca. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.