Mixed Results for Roche's Ipatasertib in Phase 3 Prostate Cancer Trial as It Meets One Co-Primary Endpoint

Compiled by Keke

Genentech, a member of the Roche Group, recently announced that the Phase 3 clinical study IPATential150 met its co-primary endpoints,ipatasertib in combination with the standard of care regimen versus the current standard of care regimen (abiraterone and prednisone/prednisolone) plus placeboProlonged radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring PTEN loss. However, the study failed to meet the other co-primary endpoint of prolonging rPFS; thus, the overall results were mixed.

IPATential150 is a double-blind, placebo-controlled, randomized Phase 3 clinical study that enrolled 1,101 male patients to evaluate the efficacy and safety of iptasertib in combination with standard of care in adult male patients with asymptomatic or mildly symptomatic, previously untreated metastatic castration-resistant prostate cancer (mCRPC). The co-primary endpoints included radiographic progression-free survival (rPFS) in the overall study population and rPFS in the subgroup with PTEN gene loss assessed by immunohistochemistry. Progression-free survival (PFS) in the study was defined as the time from the date of randomization to the first occurrence of disease progression due to any cause or death, whichever occurred earlier. Secondary endpoints included overall survival, safety, time to pain progression, time to initiation of cytotoxic chemotherapy, and time to functional deterioration.

Genentech pointed out that although the initial data is encouraging, the overall survival benefit and other secondary endpoint data are not yet mature. The trial will continue until the next analysis, at which time the data will be shared with health authorities.

Prostate cancer is one of the most common types of cancer in men. According to data from the American Cancer Society, it is estimated that there are over 190,000 prostate cancer patients in the United States. Although most male patients can be cured through local treatment, recurrence or newly diagnosed metastatic disease significantly increases morbidity and mortality. In terms of treatment, the primary therapeutic approach for advanced prostate cancer includes androgen deprivation therapy (ADT), which reduces androgen levels in the body to near-castrate levels. Although most patients with metastatic prostate cancer initially respond to ADT, other effective treatments are still required when resistance develops and the disease progresses to metastatic castration-resistant prostate cancer (mCRPC).

Loss of function of the tumor suppressor protein PTEN occurs in approximately 40%–60% of patients with metastatic castration-resistant prostate cancer (mCRPC), leading to hyperactivation of the PI3K/AKT pathway and associated with numerous adverse outcomes, including increased tumor grade and stage, early biochemical recurrence after radical prostatectomy, metastasis, and androgen-independent progression.

Ipatasertib is an oral, highly specific investigational drug designed to target and bind all three isoforms of AKT (also known as protein kinase B), thereby blocking the PI3K/AKT signaling pathway, a key driver of prostate cancer cell growth and proliferation.

Research on pharmacological therapies targeting AKT has remained discouraging. Due to safety concerns, GlaxoSmithKline halted the development of GSK690693, and Merck’s MK-2206 also demonstrated suboptimal efficacy. The failures of these AKT inhibitors have positioned ipatasertib as a frontrunner in the field, with Roche’s primary competitor now being AstraZeneca’s small-molecule AKT inhibitor, capivasertib.

Ipatasertib was jointly discovered by Genentech and Array BioPharma, the latter of which was acquired by Pfizer in July 2019. Currently, the clinical development program for this candidate drug is primarily focused on tumors with activation of the PI3K/AKT pathway. In addition to prostate cancer, three major studies are underway in various types of breast cancer, including triple-negative breast cancer and hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Results are expected in the second half of 2020.

Given that PTEN loss occurs in approximately half of patients with metastatic castration-resistant prostate cancer (mCRPC), the patient subpopulation is sufficiently large to offer ipatasertib viable commercial prospects. Sell-side consensus data from EvaluatePharma project ipatasertib’s revenue to reach $1.3 billion by 2026. Roche is reportedly planning to submit regulatory applications for ipatasertib in the treatment of prostate and breast cancers this year.

However, without further support for benefit in the overall population, it will undoubtedly be necessary to address changes to the standard of care, requiring PTEN testing for prostate cancer patients receiving ipatasertib; therefore, the outlook for ipatasertib remains less than optimistic.

Reference Source: Genentech’s IPATential150 Study Evaluating Ipatasertib in Combination With Abiraterone and Prednisone/Prednisolone Met One of Its Co-Primary Endpoints