Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. The phase 3 IPATential 150 trial demonstrates that mCRPC tumours with PTEN loss are sensitive to a dual blockade with both abiraterone/prednisolone and the AKT inhibitor ipatasertib.

 

About 40%-50% of mCRPC tumours show loss of the AKT phosphatase PTEN, which leads to hyperactivation of the oncogenic PI3K/AKT signalling pathway. In addition, it has been demonstrated that, due to reciprocal cross talk, blockade of the androgen receptor (AR)-activated pathway activates the PI3K/AKT signalling pathway, enabling prostate cancer cell survival [1]. Therefore, PTEN loss in mCRPC is associated with worse prognosis and reduced benefit of AR blockade. A phase 2 study of dual AR and PI3K/AKT inhibition with abiraterone/prednisolone and the AKT inhibitor ipatasertib resulted in a prolonged radiographic progression-free survival (rPFS) versus abiraterone/prednisolone alone, especially in mCRPC patients with PTEN-loss tumours [2].

 

The randomised phase 3 IPATential 150 trial was designed to evaluate the efficacy and safety of ipatasertib with abiraterone/prednisolone in patients with previously untreated mCRPC. A total of 1,101 patients with asymptomatic or mildly symptomatic mCRPC who had no prior treatment for mCRPC were 1:1 randomised to receive ipatasertib (400 mg/day) plus abiraterone (1,000 mg/day) and prednisone (5 mg BID) or placebo plus abiraterone and prednisone. Patients were stratified to PTEN loss as determined by immunohistochemistry (≥50% of the tumour cells having no detectable PTEN staining). Coprimary endpoints were investigator-assessed rPFS in intention-to-treat (ITT; n=1,101) and PTEN-loss (n=521) populations. Secondary endpoints included time to PSA progression, PSA response rate, confirmed objective response rate (by RECIST 1.1) in ITT patients and patients with PTEN loss, and rPFS in patients with PTEN-loss tumours by next-generation sequencing (NGS). Prof. Johan de Bono (Royal Marsden Hospital, UK) presented the first results [3].

 

The primary endpoint of the study was met in the PTEN-loss population. Median rPFS was statistically significant better in the ipatasertib arm compared with controls: 18.5 months versus 16.5 months (HR 0.77; P=0.0335). Median rPFS in the ITT population (19.2 months versus 16.6 months; HR 0.77; P=0.043) did not meet the prespecified significance level. In the prespecified subgroup analysis of patients with PTEN loss by NGS (n=208), median rPFS was 19.1 months in the ipatasertib arm versus 14.2 months in the placebo arm (HR 0.65; P=0.02). Secondary endpoints favoured the combination arm: ORR increased from 39% to 84%, PSA response rate increased from 72% to 84%, and time to PSA progression increased from 7.6 months to 12.6 months in the PTEN-loss population. Data on time to pain progression, time to initiation of chemotherapy, as well as overall survival are not yet mature.

 

Treatment with ipatasertib plus abiraterone/placebo was associated with more toxicity, leading to dose reduction in 39.9% of the patients (versus 6.2% in the placebo arm) and discontinuation in 21.1% of the patients (versus 5.1% in the placebo arm). Most prominent adverse events were diarrhoea, hyperglycaemia, and skin rash.

 

In conclusion, first-line dual AR/AKT blockade with ipatasertib plus abiraterone/prednisolone improved clinical outcome over AR blockade alone in mCRPC patients with PTEN loss, a poor prognosis population.

 

  1. Carver BS, et al. Reciprocal feedback regulation of PI3K and androgen receptor signalling in PTEN-deficient prostate cancer. Cancer Cell 2011; 19: 575-586.
  2. De Bono JS, 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: 928-936.
  3. De Bono JS, et al. IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). ESMO 2020 Virtual, abstract LBA4.