Ipatasertib Plus Abiraterone Improves Progression-Free Survival in Prostate Cancer Subtype

Ipatasertib plus abiraterone (Zytiga) was associated with improved radiographical progression-free survival (PFS) in patients with metastatic castrate-resistance prostate cancer (mCRPC) and PTEN-loss tumors, according to data from the ongoing IPATential150 trial (NCT03072238), published in Lancet.

Of note, the same improvement was not statistically significant in the intention-to-treat population. Adverse events (AEs) reflected previously reported safety profiles.

At the median follow-up at 19 months, the median radiographical PFS was 18.5 months (95% CI, 16.3-22.1) in the experimental arm and 16.5 months (95% CI, 13.9-17.0) in the control arm (HR, 0.77; 95% CI, 0.61-0.98; P = .034). Median PFS in the intention-to-treat population was 16.6 months in the control group and 19.2 months in the experimental group (HR, 0.84; 95% CI, 0.71-0.99; P = .043).

“Overall, our findings confirm that combined AKT and androgen-receptor signaling pathway blockade with ipatasertib plus abiraterone is superior to androgen-receptor signaling pathway blockade alone with abiraterone in patients with mCRPC with PTEN loss, as previously observed in the phase 2 study,” wrote the investigators. “This trial is, to our knowledge, the first to provide comprehensive phase 3 data confirming the role of simultaneous AKT and androgen- receptor signaling pathway inhibition.”

The study included 1611 patients with generally balanced baseline characteristics who were divided equally into investigative and control arms. Roughly 18% of the participants had received prior taxane-based therapy for hormone-sensitive prostate cancer, and 14% had visceral metastases, including lung, liver, or a combination of both. The participants consisted of 561 (51%) European patients, 277 (25%) Asian-Pacific, 144 (13%) North American, and 119 (11%) other populations.

Secondary end points assessed overall survival, time to prostate specific antigen (PSA) progression, PSA response rate, and objective response rate.

Around 47% of patients had experienced PTEN loss by immunohistochemistry. Among this population, the PSA response rate was 11.8% (95% CI, 4.3-19.3) greater in the experimental arm (83%) than in the control arm (72%).The difference was less significant in the intention-to-treat population, where the PSA response rate between the ipatasertib and placebo group was 5.9%.

In addition, the median time to PSA progression was greater with ipatasertib in both the PTEN-loss-by-immunohistochemistry and intention-to-treat population.

Overall, AEs were observed in 70% of patients treated with the ipatasertib-abiraterone combination.Treatment was discontinued in 5% of the placebo group and 21% of the ipatasertib group in response to AEs. Two patients died in relation to the AEs from both the placebo and ipatasertib group.

One limitation that the authors noted was that most of the tumor samples were archival, and a percentage of patients might have developed PTEN loss during the time between sample collection and initiation of study treatment. Furthermore, next-generation sequencing could not determine the PTEN status of several tumor samples.The authors argued that the strong collaboration with independent assessments helped validate the investigator assessment of radiographical progression, which was therefore not a limitation.

The study authors concluded that “this study did not reveal a benefit with ipatasertib in the overall population but confirmed that combined AKT and androgen-receptor signaling pathways blockade with ipatasertib and abiraterone provided a significantly reduced risk of radiographical disease progression or death and improved clinical outcomes compared with androgen-receptor blockade alone with abiraterone in men with mCRPC with PTEN loss—a large subgroup of patients who have poor prognosis.”

The authors stated that future studies should evaluate the effect of early and optimal prophylactic measures to prevent the need for drug discontinuation.

Reference

Sweeny C, Bracarda S, Sternberg CN, et al.Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150):
a multicentre, randomised, double-blind, phase 3 trial. Lancet 2021; 398: 131–42. https://doi.org/10.1016/S0140-6736(21)00580-8