Addition of Capivasertib to Chemotherapy May Not Be Beneficial in mCRPC

Article

Composite progression-free survival was not prolonged in patients with metastatic castration-resistant prostate cancer when the AKT kinase inhibitor capivasertib was added to chemotherapy. Despite this result, the combination demonstrated favorable overall survival.

Composite progression-free survival (cPFS) was not prolonged in patients with metastatic castration-resistant prostate cancer (mCRPC) when the AKT kinase inhibitor capivasertib (AZD5363) was added to chemotherapy. Despite this result, the combination demonstrated favorable overall survival (OS), results published in the Journal of Clinical Oncology show.

Investigators led by Simon J. Crabb, PhD, hypothesized a positive result for this study based on data observed with capivasertib as monotherapy across multiple solid tumors. The agent most notably demonstrated a 46% reduction in the size of PIK3CA-mutant breast tumors and a 56% tumor size reduction in PIK3CA-mutant gynecologic cancers, according to prior study results. Treatment with single-agent capivasertib also demonstrated clinical activity when used as treatment of AKT1-mutant solid cancers. Despite the potential observed with capivasertib, Crabb et al do not recommend the use of capivasertib with chemotherapy now that the multicenter, randomized, double-blind, placebo-controlled ProCAID trial has concluded. However, further prospective validation would be necessary to exclude the potential for bias in the study.

The patients enrolled were at least 18 years of age with an ECOG performance status 0-1, and who were suitable for treatment with docetaxel and prednisolone. All patients enrolled had progressive mCRPC and their previous therapies were not restricted to any specific hormonal therapy.

Patients were randomized 1:1 to received either the combination of capivasertib 320 mg twice daily in a 4-days-on/3-days-off continuous schedule, or a matching placebo, with chemotherapy. Patients also received up to 10 cycles of docetaxel and prednisolone in 21-day cycles. Docetaxel was administered at 75 mg/m2 and prednisone was administered at 5 or 10 mg. Premedication and antiemetic prophylaxis was allowed.

Investigator-assessed cPFS was the primary end point of the study, and the secondary end points included overall survival (OS), PFS excluding prostate-specific antigen (PSA) progression alone, PSA-based PFS, PSA response, bone changes, and safety. To evaluate the study outcomes, patients were stratified by the presence of bone metastases, visceral disease, prior use of abiraterone acetate (Zytiga) or enzalutamide (Xtandi), and investigational site.

The cPFS outcome was calculated from the time of randomization to disease progression. The study was 90% powered to detect a 50% improvement in the median cPFS from 6 months to 9 months. Efficacy was assessed in the intention-to-treat (ITT) population, which included 150 patients. Safety was analyzed in the full study population.

At a median follow-up of 23.7 months (reverse Kaplan-Meier method, interquartile range [IQR], 14.4-31.0), the median cPFS observed with capivasertib/chemotherapy was 7.03 months (95% CI, 6.28-8.25) versus 6.7 months (95% CI, 5.52-7.36) with chemotherapy/placebo. In total, 135 PFS events occurred in the study including 89.3% in the capivasertib arm and 90.7% in the placebo arm; PFS events included PSA progression in

82.1% versus 80.9% of patients, respectively. Overall, capivasertib added to chemotherapy did not lower the risk of progression or death, with an adjusted HR of 0.92 (80% CI, 0.73-1.16, one-sided P = .32). At 6 months, the PFS rate was 62% for the capivasertib/chemotherapy arm versus 56% for the placebo arm.

The median OS rate observed with the addition of capivasertib to chemotherapy was 31.15 months (95% CI, 20.07-not reached) compared with 20.27 months (95% CI, 17.51-24.18) in the placebo arm. Capivasertib/chemotherapy led to a 46% reduction in overall risk of death, with an adjusted HR of 0.54 (95% CI,0.34-0.88, two-sided = .01). At 2 years, the OS rate was 56% with capivasertib versus 39% without. The most common cause of death was prostate cancer for 83.3% of patients in the capivasertib arm versus 90.5% in the placebo arm.

The safety analysis showed a minimum of 1 adverse event (AE) in every patient assessed. Grade 3 or higher AEs were observed in 62.2% of patients in both arms. At least 1 of the AEs were related to treatment with the combination of capivasertib and chemotherapy in 81.0% of patients. No grade 5 events were seen. Treatment discontinuation did occur in the study for 23.0% of patients in the capivasertib arm and 10.8% of the placebo arm.

In a biomarker analysis, Crabb et al assessed how baseline circulating tumor DNA next-generation sequencing results impact survival and response to therapy in the study.

In addition to not showing a difference in PSA response based on PI3K/AKT/PTEN pathway activation status, PFS and OS were also not significantly changed in patients with different sites of disease, prior treatment, Gleason score, PSA levels, and laboratory results.

In terms of PSA response rates, the capivasertib arm had a rate of 45% (95% CI, 34%-57%) compared with 55% (95% CI, 44%-66%) in the placebo arm (odds ratio, 0.66; 95% CI, 0.35-1.26, P = .207). Overall, PFS and PSA-based PFS in the ITT group did not differ across the treatment arms, with PSA progression alone and new anti-prostate cancer treatment being the 2 exceptions.

Crabb et al noted that although the trial was negative for its primary end point, the secondary end point of OS was positive. They wrote: “To address the apparent discordance in this result would require prospective validation studies that should focus on identification of patients most likely to benefit.”

Reference:

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

Related Videos
Related Content