New Drug for Prostate Cancer: Ipatasertib, an AKT Inhibitor

Neil Osterweil

September 24, 2020

The investigational kinase inhibitor ipatasertib (Roche), which targets a key cancer metabolic pathway, has shown promise when used in combination with abiraterone (Zytiga) in the treatment of patients with untreated asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC).

New results with the combination were presented online during the European Society of Medical Oncology (ESMO) Virtual Congress 2020.

The combination is promising but isn't quite ready for the clinic, commented invited discussant Henrik Grönberg MD, PhD, from the Karolinska Institute in Stockholm, Sweden.

The new results come from the phase 3 IPATential 150 trial, which met only one of its two primary endpoints, investigators noted.

The combination of ipatasertib and abiraterone improved radiographic progression-free survival (rPFS) for patients with mCRPC with PTEN loss, as assessed with immunohistochemistry (IHC), in comparison with abiraterone alone.

But the trial failed to meet its other primary endpoint of rPFS in the intention-to-treat (ITT) population, which included patients without IHC evidence of PTEN loss, reported Johann De Bono, MD, PhD, from the Institute of Cancer Research at the Royal Marsden Hospital in London, United Kingdom.

"In this primary analysis, the combination of ipatasertib plus abiraterone as a first-line treatment for mCRPC resulted in significantly superior radiologic progression-free survival and antitumor activity compared with placebo plus abiraterone in patients with PTEN loss, first-line mCRPC," he said.

PTEN loss occurs in about 40% to 50% of mCRPC cases. Loss of the gene leads to activation of the PI3K/AKT pathway and is associated with worse prognosis and reduced benefit from androgen receptor (AR) blockade.

Interestingly, among patients with PTEN loss, assessment of rPFS using next-generation sequencing (NGS) rather than by IHC showed a wider separation of survival curves in favor of the combination.

"I think it's very promising data on AKT inhibition in prostate cancer, particularly in the NGS-defined group of PTEN loss," commented Grönberg in his discussion of the trial.

"But I think it's too early; the subgroup that benefits from this treatment needs to be defined better, and we need to also see more mature data from this very important trial," he added.

New Approach: AKT Inhibitor

Ipatasertib is an oral small molecule that binds to the adenosine triphosphate (ATP)-binding pocket of all three isoforms of AKT. The drug inhibits AKT serine-threonine kinase activity and has been shown to improve the antitumor effects of AR blockade in prostate cancer models, De Bono explained.

"Reciprocal cross-talk has been demonstrated between AR signaling and PI3K/AKT signaling, enabling prostate cancer cell survival, while dual blockade has superior antitumor activity," he said.

Study Details

For the IPATential 150 trial, the investigators enrolled 1101 patients with asymptomatic or only mildly symptomatic mCRPC who had not been treated for advanced disease. The patients included 521 with PTEN loss and 580 who had no evidence of PTEN loss.

Patients were stratified by PTEN loss by IHC, prior taxane therapy, progression by prostate-specific antigen (PSA) only, presence of liver and/or lung metastases, and geographic region. They were randomly assigned to receive abiraterone 1000 mg daily plus either ipatasertib 400 mg daily (547 patients) or placebo (554 patients).

After a median follow-up of 19 months, the median rPFS for patients with PTEN loss by IHC who underwent treatment with the combination was 18.5 months, compared with 16.5 months for patients treated with abiraterone alone.

The 1-year event-free rate was 64.4% with the combination, compared with 63.3% with abiraterone alone, translating into a stratified hazard ratio (HR) for progression with ipatasertib plus abiraterone of 0.77 (P = .0335).

In the ITT population, median rPFS was 19.2 months with ipatasertib/abiraterone, vs 16.6 months with abiraterone/placebo. The respective 1-year event-free rates were 65.3% and 63.0%, translating into an HR of 0.84 for the combination. However, the P value (.0431) for this analysis did not reach the prespecified P value for statistical significance, which was .01, meaning that this coprimary endpoint was not met.

As noted, rPFS in the PTEN-loss population, as defined by NGS, was a secondary endpoint. It was 19.1 months with the combination, vs 14.2 months with abiraterone/placebo, translating into an HR favoring the combination of 0.65 (P = .0206).

Better Objective, PSA Responses

Response rates with the combination were much higher than with abiraterone alone.

In the PTEN loss analysis, objective response rates, determined in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, were 61% for patients who received ipatasertib plus abiraterone, vs 39% for those who received abiraterone alone. The respective rates in the ITT population were 61% and 44%.

Biochemical PSA response rates in the PTEN loss by IHC group were 84% vs 72%. In the ITT group, they were 81% vs 76%.

Time to PSA progression was also significantly better in the combination arm in both analyses. The HR was 0.69 (P = .0013) in the PTEN-loss population and 0.73 (P < .0001) in the ITT population.

There were no significant differences by treatment arm or population in time to initiation of cytotoxic chemotherapy, however.

Overall survival data were not mature at the time of data cutoff. In the current analysis, there was no difference in overall survival between treatment arms, De Bono said.

Toxicities Higher With Ipatasertib

Grade 3 or 4 adverse events were reported in 70.1% of patients treated with ipatasertib/abiraterone, vs 39% for those treated with abiraterone and placebo. Twenty-four patients (4.4%) who were treated with the combination died during the study, as did 20 patients (3.7%) who received abiraterone alone.

Adverse events leading to discontinuation of study treatment occurred in 21.1% of patients in the combination arm and 5.1% of patients in the placebo arm. Adverse events leading to dose reductions occurred in 39.9% and 6.2%, respectively.

Adverse events with a 2% or greater difference between treatment arms ― all of which occurred at higher rates among patients treated with the combination ― included rash/maculopapular rash, diarrhea, hyperglycemia, elevated liver transaminase levels, and dehydration.

De Bono noted that drug discontinuations may be avoided by use of prophylactic loperamide for diarrhea and antihistamine for preventing or ameliorating cutaneous adverse events.

Do Taxanes Affect AKT Inhibition?

In his discussion, Grönberg pointed out that only about 18% of patients in each arm had received prior therapy with taxanes, a lower percentage than typically seen in practice.

"An interesting observation ― when we look at prior taxane-based therapy, in those exposed to taxanes before, there was no effect on PFS compared to those who were not exposed to taxane-based therapy," he said.

This finding raises the possibility that prior taxane therapy can make patients less sensitive to AKT inhibitors, which should be explored further, he added.

He also pointed to the rPFS analysis by NGS, which was conducted in only 205 of 1101 patients.

"In my view, most likely NGS is a better way to define PTEN loss, and I urge the authors and the company to try to collect [NGS data for] the other 900 patients to do this analysis," Grönberg said.

The study was funded by F. Hoffmann-La Roche. De Bono disclosed honoraria for advisory boards and/or lectures and research grants from Hoffmann-La Roche and others. Grönberg disclosed honoraria from Astellas Pharma, Janssen Oncology, and Bayer HealthCare.

European Society for Medical Oncology (ESMO) Annual Meeting 2020: Abstract LBA4, presented September 20, 2020.

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