Adding ipatasertib to abiraterone improves clinical outcomes in patients with metastatic castration-resistant prostate cancer and PTEN-loss

Results of the phase III IPATential150 trial, presented as a late breaking abstract during ESMO 2020, demonstrated that dual targeting with ipatasertib and abiraterone as first-line treatment for metastatic castration-resistant prostate cancer (mCRPC) resulted in significantly improved radiographic progression-free survival (rPFS) compared to placebo plus abiraterone in patients with mCRPC and PTEN loss of function (HR[95%CI]: 0.77[0.61-0.98], p=0.0335). In addition to this, the ipatasertib-abiraterone combination was associated with an improved objective response rate as well as improved time to PSA progression and PSA response.

Introduction

Overall, 40-50% of patients with mCRPC display loss of function of the AKT phosphatase and tensin homologue (PTEN), resulting in a hyperactivation of the oncogenic PI3K/AKT signalling pathway. PTEN loss in mCRPC is associated with worse prognosis and a reduced benefit from androgen receptor (AR) blockade. In addition, reciprocal crosstalk has been demonstrated between AR and PI3K/AKT signalling, in which AR blockade can activate PI3K/AKT signalling, enabling prostate cancer cell survival. Based on these findings, dual targeting of both pathways has been hypothesized to increase the anti-tumour activity. Ipatasertib is an oral investigational small molecule that binds to the ATP-binding pocket of all three isoforms of AKT, thereby inhibiting the AKT serine-threonine kinase activity and improving the anti-tumour activity of AR blockade in prostate cancer models.

Previously, a phase II study of dual AR and PI3K/AKT inhibition with abiraterone and ipatasertib demonstrated a prolonged rPFS compared to AR inhibition alone, with a greater impact observed among patients with PTEN-loss tumours. The phase III IPATential150 randomised, double-blind study was designed to evaluate the efficacy and safety of adding ipatasertib to abiraterone in asymptomatic or mildly symptomatic patients previously untreated for mCRPC. In total, 1,101 patients with mCRPC were randomised (1:1) to receive ipatasertib (400 mg/d) plus abiraterone (1,000 mg/d) plus prednisone/prednisolone (5 mg, twice daily) or placebo plus abiraterone plus prednisone/prednisolone until radiographically assessed disease progression. Demographics and baseline characteristics were well balanced between study arms in both the intention-to-treat (ITT) population (N=1,101) as well as the PTEN-loss group (N=521).

Results

At the time of the data cut-off (March 2020), approximately one third of patients in both treatment arms were still on treatment. After a median follow-up of 19 months, the median rPFS for patients with PTEN-loss (defined as a minimum of 50% of the specimen’s tumour area with no detectable PTEN staining) was 18.5 months in the ipatasertib arm, as compared to 16.5 months for patients in the control arm (HR[95%CI]: 0.77[0.61-0.98], p= 0.0335). In this PTEN-loss cohort, the addition of ipatasertib to abiraterone was associated with a significant rPFS improvement across all investigated subgroups. In the ITT population, the rPFS was reported at 19.2 months with ipatasertib as compared to 16.6 months with placebo (HR[95%CI]: 0.84[0.71-0.99], p= 0.0431). However, this difference did not reach the threshold for statistical significance that was pre-set at p< 0.01.

The objective response rate (ORR) was higher for ipatasertib-abiraterone compared to abiraterone-placebo, both in the PTEN-loss cohort as in the ITT population (61% vs. 39% and 61% vs. 44%, respectively). An improved PSA response rate was also observed with the ipatasertib-containing treatment in both the PTEN-loss subgroup (improvement of 11.8%) as in ITT population (5.9%), with descriptive p-values of respectively 0.0012 and 0.0183. Finally, the addition of ipatasertib to abiraterone was also associated with a significantly delayed time to PSA progression (12.6 vs. 7.6 months and 12.9 vs. 8.4 months in the PTEN-loss and ITT populations, respectively). Data for time to pain progression, time to initiation of cytotoxic chemotherapy and overall survival are still immature, but all seem in favour of the dual inhibition strategy.

The increased efficacy of the combination did come at the cost of more toxicity. Overall, 39.9% of patients in the ipatasertib plus abiraterone arm and 6.2% of patients in the control arm experienced an adverse event leading to a dose reduction of ipatasertib or placebo. Moreover, 21.1% of patients discontinued ipatasertib due to AEs, while only 5.1% of patients in the control arm had to discontinue their treatment. This was mainly due to skin rash, diarrhoea, hyperglycaemia or increased alanine aminotransferase or aspartate aminotransferase levels.

Conclusion

In this primary endpoint analysis of the IPATential150 trial, adding ipatasertib to abiraterone in the first-line treatment of patients with mCRPC resulted in significantly improved rPFS in patients with PTEN-loss. In the ITT population, this benefit did not reach statistical significance. In addition, ipatasertib was also associated with an improved time to PSA progression, a higher PSA response and a higher ORR in patients with measurable disease at baseline. However, in line with known and potential risks, an increased toxicity was observed with the addition of ipatasertib to abiraterone, with a high proportion of patients requiring dose alterations.

Reference

De Bono J, Bracarda S, Sternberg CN, et al. IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). Presented at ESMO 2020; Abstract LBA4.