Ipatasertib - Phase III study with Abiraterone,

[pjoshea13]

New study below [1]

Ipatasertib is an AKT inhibitor. The PI3K-AKT pathway is often activated in PCa cells & is associated with proliferation.

The PTEN (tumour suppressor gene) is often silenced in PCa cells.

Johann S. de Bono (Royal Marsden) was the author of a Feb 2019 paper [2]:

"Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss"

"In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors."

So it's no great surprise to discover that:

"Phase 3 data showed that the addition of the AKT inhibitor ipatasertib to standard therapy boosted radiographic progression-free survival in patients with advanced castration-resistant prostate cancer whose tumors had PTEN loss."

However, the study: "did not meet the other coprimary end point of rPFS {radiographic progression-free surviva} in the overall study population."

"The double-blind phase 3 IPATential150 trial accrued adult male patients with asymptomatic or mildly symptomatic, previously untreated mCRPC. Patients were randomized to abiraterone and prednisone/prednisolone plus either ipatasertib or placebo. Beyond the rPFS coprimary end points, secondary end points include overall survival, safety, time to pain progression, time to initiation of cytotoxic chemotherapy, and time to function deterioration."

Systemic Akt inhibition is not desirable in those who will not benefit. Looks like a tumor biopsy is needed to determine the probability of benefit. IMO

-Patrick

[1] urologytimes.com/view/ipata...

[2] clincancerres.aacrjournals....

Adding the AKT inhibitor ipatasertib to abiraterone acetate (Zytiga) and prednisone improved radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) whose tumors had PTEN loss, meeting a coprimary end point of the phase 3 IPATential150 study.1

The triplet, however, did not meet the other coprimary end point of rPFS in the overall study population (ITT). Roche (Genentech), the developer of ipatasertib, also noted in a press release that, “While initial data are encouraging, overall survival (OS) benefit and additional secondary end points are not yet mature.”

The company also noted in the press release that no new safety signals emerged with the combination regimen in the phase 3 study. No data were made available at this time, with Roche planning to share the results at a future medical conference.

“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, Roche’s chief medical officer and head of global product development, stated in a 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 a small molecule inhibitor of all 3 isoforms of AKT. Obstructing these isoforms blocks the PI3K/AKT signaling pathway, which is hypothesized to stop the proliferation and survival of tumor cells.

The double-blind phase 3 IPATential150 trial accrued adult male patients with asymptomatic or mildly symptomatic, previously untreated mCRPC. Patients were randomized to abiraterone and prednisone/prednisolone plus either ipatasertib or placebo. Beyond the rPFS coprimary end points, secondary end points include overall survival, safety, time to pain progression, time to initiation of cytotoxic chemotherapy, and time to function deterioration.

Phase 1b/2 data for the combination of ipatasertib and abiraterone/prednisone in patients with metastatic or advanced prostate cancer were previously published in Clinical Cancer Research.2 The study accrued patients aged ≥18 years who had an ECOG performance status of 0 or 1. Patients had prior docetaxel and disease progression following at least 1 hormonal therapy. Patients were also required to have adequate liver, hematologic, and kidney function at baseline.

In the study, patients were randomized to 1 of 3 arms: ipatasertib (400 mg) plus abiraterone (1000 mg) and prednisone/prednisolone (n = 84); ipatasertib (200 mg) plus abiraterone (1000 mg) and prednisone/prednisolone (n = 87); or placebo plus abiraterone (1000 mg) and prednisone/prednisolone (n = 82). The coprimary end points were the same as in the phase 3 trial: rPFS in the ITT population and in the subgroup of patients whose tumors had PTEN loss.

The results showed an rPFS benefit with the addition of ipatasertib to abiraterone/prednisone, regardless of PTEN status; however, the benefit was greater in patients with PTEN-loss tumors. In the ITT population, the median rPFS was 8.18 months in the 400-mg ipatasertib arm versus 6.37 months in the placebo arm (HR, 0.75; 90% CI, 0.54-1.05; P = .17). In the 200-mg ipatasertib arm, the rPFS was 8.31 months (HR vs placebo, 0.94 ; 90% CI, 0.69-1.28; P = 0.75).

Regarding OS in the ITT group, the median OS in the 400-mg arm was 18.92 months compared to 15.64 months in the control arm (HR, 0.72; 90% CI, 0.47-1.11; P = 0.22). The median OS was 21.5 months with the lower-dose of ipatasertib (HR vs placebo, 0.94; 90% CI, 0.65-1.43; P = 0.88).

The rPFS boost with ipatasertib was much more pronounced in the PTEN-loss population. Among patients with PTEN-loss tumors who received the 400-mg ipatasertib dose, the median rPFS was 11.5 months versus 4.6 months in the control arm (HR, 0.39; 90% CI, 0.22-0.70). In patients without PTEN loss, the median rPFS was 7.5 versus 5.6 months, respectively (0.84; 90% CI, 0.51-1.37).

In the 200-mg ipatasertib arm, the median rPFS was 11.1 months in the PTEN-loss group (HR vs placebo, 0.46; 90% CI, 0.25-0.83). The median rPFS was 5.6 months with the lower ipatasertib dose in the subgroup without PTEN loss (HR vs placebo, 1.13; 90% CI, 0.69-1.85).

References

1. Roche’s IPATential150 study evaluating ipatasertib in combination with abiraterone and prednisone/prednisolone met one of its co-primary endpoints. Published June 19, 2020. bit.ly/2Nei0Wk. Accessed June 19, 2020.

2. Bono JS, Giorgi UD, Rodrigues DN, et al. Randomized phase II study evaluating Akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res. 2019;25(3):928-936. doi: 10.1158/1078-0432.CCR-18-0981

[tango65]

The combination have a lot of negative side effects:

"AEs were more common with ipatasertib versus placebo and

were generally consistent with the PI3K–Akt–mTOR pathway

inhibitor class and included diarrhea, nausea, vomiting, asthenia, rash (grouped term), decreased appetite, and hyperglycemia (Table 3, Supplementary Table S8). Fifty-four patients (64.3%), 44 patients (50.6%), and 29 patients (35.4%) experienced a grade 3 AE in the ipatasertib 400 mg, ipatasertib 200 mg, and placebo cohorts, respectively. "

Perhaps it could be used in patients with cancers with PTEN loss, since rPFS was 11.5 months versus 4.6 months meanwhile in patients with cancers without PTEN loss, the median rPFS was only 7.5 versus 5.6 months for placebo,

[pjoshea13]

Nala,

You had prostatic tissue tested? I imagine that some men lose PTEN later. A met biopsy would find out. But you know your PTEN status, so Ipatasertib + Abi might be an option later. My guess is that the FDA will approve it for PTEN men - 40-60% of the advanced PCa population.

I suppose that Ipatasertib + Enza would be useful too.

-Patrick