A study of capivasertib plus chemotherapy did show a statistically significant extension in overall survival despite not reaching the primary end point of progression-free survival, suggesting a need for prospective validation studies to determine the reasoning behind the observed differences in these results.
Results from the phase 2 ProCAID trial (NCT02121639) indicated that the addition of capivasertib (AZD5363) to chemotherapy resulted in a statistically significant extension in the secondary end point of overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC), reducing the risk of death by 46% versus chemotherapy alone.
did not extend composite progression-free survival (cPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of their PI3K/AKT/PTEN pathway activation status.
However, investigators did observe that the experimental combination did not extend composite progression-free survival (cPFS). Both OS and cPFS results were noted regardless of patient’s PI3K/AKT/PTEN pathway activation status.
These findings, published in the Journal of Clinical Oncology, will require prospective validation studies in order to determine the reasoning behind the observed differences in these results, focusing as well on patients who would be most likely to benefit.
“Data from this study do not provide a definitive explanation for why the addition of capivasertib to chemotherapy might extend OS but not PFS,” wrote the study authors, who were led by Simon J. Crabb, PhD. “Furthermore, PSA response rates, although not statistically significantly different, favored the placebo arm numerically, and survival outcomes were found to be consistent irrespective of PI3K/AKT/PTEN pathway activation status.”
In the investigator-initiated, multicenter, double-blind, placebo controlled, randomized phase 2 trial, patients received up to 10 21-day cycles of docetaxel at a dose of 75 mg/m2 intravenously on day 1 and oral prednisolone at a dose of 5 mg twice daily on days 1 through 21. Participants were then randomly assigned 1:1 to either oral capivasertib at a dose of 320 mg twice daily (4 days on/3 days off, from day 2 of each cycle) or placebo until disease progression. In total, 150 patients were enrolled onto the study.
The primary end point was investigator-assessed cPFS, calculated as time from random assignment to disease progression or death. Secondary end points included OS,PFS excluding PSA progression alone, prostate specific antigen (PSA)–-based PFS, PSA response, bone pain changes, and safety.
Median cPFS was found to be 7.03 months (95% CI, 6.28-8.25) with capivasertib compared with 6.70 months (95% CI, 5.52-7.36) with placebo (HR, 0.92; 80% CI, 0.73-1.16; one-sided P = .32). Moreover, median OS was 31.15 (95% CI, 20.07-not reached) with capivasertib and 20.27 months (95% CI, 17.51-24.18) with placebo (HR, 0.54; 95% CI, 0.34-0.88; two-sided P = .01).
Importantly, the observed cPFS and OS results were consistent regardless of PI3K/AKT/PTEN pathway activation status.
“We acknowledge the possibility that our results, indicating an OS extension despite no PFS impact, might be spurious and are challenging to explain. In addition, the OS data remain relatively immature at this planned primary analysis,” noted the authors. “Although the size of the OS benefit observed is enticing, the possibility that biases, whether identifiable or not, might have impacted our results should be recognized.”
Regarding safety, grade 3/4 adverse events (AEs) were identical between the 2 study arms (62.2%). Consistent with prior data, the addition of capivasertib to docetaxel and prednisolone resulted in an acceptable safety profile.
The most common AEs of any grade believed to be related to capivasertib were diarrhea, fatigue, nausea, and rash. According to the investigators, these AEs are expected for capivasertib and are common across PI3K and AKT inhibitors, warranting consideration of mitigation strategies in the future development of this treatment combination.
Crabb SJ, Griffiths G, Marwood E, et al. Pan-AKT inhibitor capivasertib with docetaxel and prednisolone in metastatic castration-resistant prostate cancer: A randomized, placebo-controlled phase II trial (ProCAID). J Clin Oncol. 2021;39(3):190-201. doi: 10.1200/JCO.20.01576