Ipatasertib/Abiraterone Regimen Improves Radiographic PFS in mCRPC With PTEN Loss

Levi Garraway, MD, PhD

The combination of ipatasertib plus abiraterone acetate (Zytiga) and prednisone/prednisolone improved radiographic progression-free survival (rPFS) compared with standard treatment plus placebo in patients with metastatic castration-resistant prostate cancer (mCRPC) who have PTEN loss, meeting one of the co-primary end points of the phase 3 IPATential150 trial (NCT03072238).¹

Results showed that the ipatasertib regimen led to a statistically significant reduction in the risk of disease progression or death compared with the standard-of-care arm. Moreover, the safety profile in the experimental arm was found to be consistent with prior studies. Full findings of the phase 3 trial will be presented at an upcoming medical meeting.

Genentech (Roche), the manufacturer of ipatasertib, stated in a press release that the overall survival (OS) benefit and additional secondary end points are immature, and that the study will continue until the next planned analysis—results of which will be shared with regulatory authorities.

“Prostate cancer remains a leading cause of death in men worldwide and patients with metastatic castration-resistant prostate cancer can be difficult to treat,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, Genentech, stated in the press release. “The early results of the IPATential150 study are encouraging in our ongoing mission to develop new treatment options for people with advanced prostate cancer.”

Ipatasertib is an oral, highly specific agent that targets and binds to all 3 isoforms of AKT, which blocks the PI3K/AKT signaling pathway, which has also been associated with resistance to antiandrogen treatment; androgen receptor (AR) inhibition is associated with an increase in AKT pathway activation.

Functional loss of PTEN in the tumor is seen in 40% to 60% of patients with mCRPC, which leads to hyperactivation of the PI3K/AKT pathway. The disease characteristic is also linked with increased tumor grade and stage, earlier biochemical recurrence following radical prostatectomy, metastasis, prostate cancer–specific death, and androgen-independent progression.

In the double-blind, placebo-controlled, randomized phase 3 IPATential150 study, investigators are assessing ipatasertib in combination with abiraterone plus prednisone/prednisolone versus placebo plus abiraterone and prednisone/prednisolone in approximately 1100 adult patients with asymptomatic or mildly symptomatic, previously untreated mCRPC.

To be eligible for enrollment, patients must have an ECOG performance status of 0 or 1, adequate hematologic and organ function within 28 days before first study treatment, and a life expectancy of at least 6 months. Patients who received prior AR inhibitors, systemic radiopharmaceuticals, and had known central nervous system metastases, among other criteria, were excluded from enrolling on the study.

Ipatasertib is given orally at 400 mg once daily on day 1 of cycle 1, while abiraterone is given orally at 1000 mg once daily plus 5 mg of twice-daily prednisone/prednisolone until disease progression or unacceptable toxicity. Treatment was given in 28-day cycles.

The co-primary end points are investigator-determined rPFS in the overall study population, as well as in those whose tumors have PTEN loss, as assessed by immunohistochemistry (IHC). Secondary end points include OS, safety, time to pain progression, time to initiation of cytotoxic chemotherapy, and time to function deterioration.

Prior findings from the phase 1/2 A. MARTIN study demonstrated early clinical activity with ipatasertib in patients with mCRPC who had received prior treatment. In the trial, Investigators randomized 253 patients with mCRPC who were previously treated with docetaxel to 3 arms: ipatasertib at 400 mg, ipatasertib at 200 mg, or placebo, all of which were given in combination with abiraterone and prednisone. PTEN expression was assessed by IHC with prospectively defined criteria, and PTEN genomic loss was detected by fluorescence in situ hybridization and next-generation sequencing.

Findings showed that, at the primary analysis, 173 rPFS events were observed; PTEN status was evaluable by IHC in 165 cases (65%) and PTEN loss was seen in 71 cases (43%). Patients with PTEN loss had improved rPFS in both ipatasertib arms compared with the placebo arm, but a greater benefit was observed with the 400-mg dose. The median rPFS was 11.5 months (HR, 0.39; 95% CI, 0.22-0.70; P = .0064), 11.1 months (HR, 0.46; 95% CI, 0.25-0.83; P = .0285), and 4.6 months in the 400-mg, 200-mg, and placebo arms, respectively.

Ipatasertib is also being evaluated in triple-negative breast cancer and hormone receptor– positive, HER2-negative breast cancer, results of which are anticipated later this year.

References

1. Genentech’s IPATential150 study evaluating ipatasertib in combination with abiraterone and prednisone/prednisolone met one of its co-primary endpoints [news release]: San Francisco, CA. Genentech (Roche). Published June 19, 2020. Accessed June 19, 2020. https://bwnews.pr/3hJoPgM.
2. De Bono JS, De Giorgi U, Massard C, et al. PTEN loss as a predictive biomarker for the Akt inhibitor ipatasertib combined with abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2016;27(suppl 6):243-265. doi:10.1093/annonc/mdw372