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Roche's Ipatasertib, Anti-Androgen Therapy Improves Outcomes in Prostate Cancer With PTEN Loss


NEW YORK – Adding Roche's AKT inhibitor ipatasertib to anti-androgen therapy may delay progression of metastatic castration-resistant prostate cancer (CRPC) better than with anti-androgen therapy alone, particularly in patients with PTEN loss, according to data presented at a conference this past weekend.

Johann De Bono from the Royal Marsden Hospital in London reported the first results from the Phase III IPATential150 trial at the European Society for Medical Oncology's Virtual Congress on Sunday. According to the data, the combination of ipatasertib, abiraterone, and prednisone significantly improved radiographic progression-free survival in metastatic CRPC compared to just anti-androgen therapy in patients with PTEN loss.

The progression-free survival difference between treatment arms was bigger in a subset of patients in whom researchers determined PTEN loss using next-generation sequencing, raising questions as to whether NGS may be a better way to identify patients with PTEN loss than immunohistochemistry.

Approximately half of metastatic CRPC patients have lost PTEN gene function, which hyperactivates the PI3K/AKT pathway and results in genomic instability. This, in turn, drives cancer. Patients with PTEN loss have worse prognosis and don't respond well to anti-androgen therapies, such as abiraterone.

Earlier, a Phase II study comparing ipatasertib, abiraterone, and prednisone against abiraterone and prednisone showed longer radiographic progression-free survival for those receiving the ipatasertib-containing regimen. Importantly, metastatic CRPC patients with PTEN loss appeared to derive greater benefit than those without this biomarker.

Based on this earlier data, Roche decided to launch the Phase III IPATential150 trial, specifically looking at the activity of the ipatasertib-abiraterone regimen in first-line metastatic CRPC. In June, Roche said that the study met its co-primary endpoint of radiographic progression-free survival in patients with PTEN loss, but not in the overall study population.

At the ESMO meeting, De Bono presented results for the first time.

The IPATential150 trial considered the efficacy and safety of Roche's ipatasertib-abiraterone against placebo-abiraterone in 1,000 metastatic castration-resistant prostate cancer. For the primary endpoint analysis of radiographic progression-free survival, PTEN loss in patients' samples was determined by a Ventana IHC assay; tumors were classified as having PTEN loss if at least 50 percent of tumor cells had no PTEN staining. There were 521 patients in the subgroup of patients with PTEN loss.

Secondary endpoints in the trial included overall survival, overall response rate, and radiographic progression-free survival in patients with PTEN loss determined by NGS.

At data cutoff on March 16, in patients with PTEN loss, the median radiographic progression-free survival was 18.5 months on the ipatasertib-containing arm and 16.5 months in the control arm. Patients receiving ipatasertib had a 23 percent lower risk of radiographic progression compared to those not receiving the drug.

In the overall population, however, median radiographic progression-free survival was 19.2 months in the ipatasertib arm versus 16.6 months in the control arm, which did not meet the pre-specified threshold for statistical significance.

When investigators considered patients who had PTEN loss according to NGS, there was a greater difference in median radiographic progression-free survival between the study arms: 19.1 months in the ipatasertib arm and 14.2 months in the control arm. Moreover, ipatasertib-treated patients had a 35 percent lower risk of radiographic progression than those not on the drug.

The NGS-based outcomes analysis is the most interesting data from the trial, according to Henrik Grönberg from the Karolinska Institute, who reviewed the data form the IPATential150 trial at the meeting. "My view is that most likely NGS is a better way to define PTEN loss," he said, noting that this analysis involved only around 200 patients. Grönberg urged Roche to collect NGS PTEN loss data on the rest of the study population and analyze outcomes accordingly.

"Biomarker-guided treatment is the future," he said. However, in the era of precision oncology treatments, drug developers should stratify patients prospectively based on the biomarkers of interest and use the best technology to do so, in his view. "We have the tools now, particularly with NGS [and] circulating tumor DNA," Grönberg said. "I'd really like to see these used to define biomarkers in future trials."

De Bono noted that researchers plan to present more detailed analysis on patients with PTEN loss based on the IHC assay with different cutoffs. In the Phase II trial evaluating ipatasertib in the metastatic CRPC setting, patients were determined to have PTEN loss if less than 10 percent of tumor cells were stained for PTEN and a different assay was used. Investigators have looked at outcomes in the trial based on different cutoffs, which will be shared in the future.

He added that the results in the NGS population confirm overall that patients with PTEN loss have improved outcomes with ipatasertib-abiraterone over abiraterone alone. However, De Bono didn't specifically address whether the companion diagnostic for this regimen should ultimately be NGS or IHC based when asked during a discussion of the study data at the meeting.

"Defining the optimal assay is obviously a challenge," he said. "If you look at HER2 [expression] in breast cancer, it took quite a long time to figure that out."

In the group with PTEN loss, objective response rates were 39 percent in the control arm and 61 percent for the ipatasertib-treated group. "This is really an impressive increase in response rate," De Bono said, noting that response rates were also higher in the ipatasertib arm in the overall population.

There are also hints of an overall survival advantage with the ipatasertib-containing regimen, he added, but the data are not mature yet, De Bono said.

In his review of the IPATential150 data, Grönberg observed that patients who receive taxane-based therapies didn't appear to experience delays in progression from ipatasertib treatment. He hypothesized that this prior taxane treatment may diminish patients' ability to respond to AKT inhibitors. "This is something we need to know more about," he said.

In terms of safety, approximately 40 percent of patients on ipatasertib experienced serious adverse events, 21 percent discontinued treatment, and 40 percent needed dose reductions as a result of treatment-related toxicities. Comparatively, 22 percent had serious adverse events, 5 percent discontinued treatment, and 6 percent needed dose reductions on the abiraterone-only arm.

The fact that patients on ipatasertib had more toxicities was not unexpected, De Bono said, noting that there were higher incidences of grade 3 or 4 diarrhea, rash, transaminase elevations, and hyperglycemia seen with this treatment. He noted that experience with similar toxicities in other trials suggest that the ipatasertib discontinuation rate may be reduced by giving drugs to patients to manage diarrhea and rash.

Overall, De Bono concluded that this trial data to date has demonstrated the ipatasertib-abiraterone regimen improves clinical outcomes over androgen receptor blocking drugs alone in metastatic CRPC patients with PTEN loss, which is a subset of patients with poor prognosis.

Roche will follow patients until overall survival and other secondary endpoints mature and share the data with healthcare authorities.

Grönberg said it's too early for him to decide whether he'd prescribe ipatasertib to his metastatic CRPC patients with PTEN loss based on the IPATential150 data. Although the NGS-based subgroup analysis is promising, he said the data needs to mature and "the subgroup that benefits from treatment needs to be defined better."