AR/AKT Combination Bests AR Blockade in mCRPC with PTEN Loss

Johann de Bono, MD

The combination of ipatasertib and abiraterone acetate (Zytiga) achieved a significantly superior radiographic progression-free survival (rPFS) and demonstrated anti-tumor activity compared with placebo and abiraterone in patients with metastatic castration resistant prostate cancer (mCRPC) with PTEN loss, according to results from the phase 3 IPATential150 clinical trial (NCT03072238).¹

Findings from the 1101-patient, randomized, double-blind, placebo-controlled, multicenter study were presented by Johann de Bono, MD, head of the Division of Clinical Studies at the Institute of Cancer Research in London, United Kingdom, who first explained that AKT signaling is one of the most import targets in advanced prostate cancer. AKT signaling is largely impacted by PTEN loss, rationalizes the need to explore a new combination strategy in this patient population.

It was shown in a 2018 study from investigators led by Tamara Jamaspishvili, MD, PhD, of the Division of Cancer Biology and Genetics, Cancer Research Institute, Queen’s University, that there are 2 key clinical implications of PTEN loss in patients with prostate cancer: shorter duration of treatment with endocrine therapy, and a poor overall prognosis. The same research led to the hypothesis that targeting PI3K–AKT–mTOR signaling and AR (androgen receptor) signaling at the same time, could be an effective strategy to address PTEN deficiency in patients with advanced prostate cancer.²

To test the theory, the AR biosynthesis inhibitor abiraterone was combined with the AKT inhibitor ipatasertib and compared with abiraterone alone. The patients were randomized 1:1 to receive either abiraterone in a placebo-controlled arm, abiraterone 1000 mg once daily (QD) plusipatasertib 400 mg QD. Patients were assessed for the co-primary end points of rPFS (radiographic progression-free survival) in patients whose tumors had PTEN loss by immunohistochemistry (IHC) in the intent-to-treat population and the PTEN loss population.¹

In the population of patients with PTEN loss by IHC, the median rPFS was 18.5 months (95% CI, 16.3-22.1) in the ipatasertib plus abiraterone arm compared with 16.5 months (95% CI, 13.9-17.0) in the abiraterone alone arm (stratified HR, 0.77; 0.51-0.95.0; P =.0335). The 1-year event-free survival rate observed in this cohort was 64.4% (95% CI, 58.3%-70.5%) with the addition ofipatasertib versus 63.3% (95% CI, 57.3%-69/3%) with abiraterone alone.

The benefit of ipatasertib plus abiraterone in patients with PTEN translated to most of the subgroups assessed, with the exception of patients with an ECOG status of 0, those aged 75 years or older, those who did not have prior taxane-based therapy, and those who had liver or lung metastases.

The rPFS data from IPATential150 appeared to be consistent with the benefit of ipatasertib plus abiraterone observed in a previously published phase 2 clinical trial (A.MARTIN, NCT01485861). The study included 253 patients with metastatic or advanced prostate cancer who received prior docetaxel and progressed on more than 1 hormonal therapy. The patients also had an ECOG performance status of 0-1.

In patients with PTEN loss assessed in the A.MARTIN study, the median rPFS observed with ipatasertib plus abiraterone was 11.5 months compared with the 4.5 months rPFS observed with abiraterone alone (HR, 0.39; 95% CI, 0.22-0.70). Among patients without PTEN loss, the median rPFS was 7.5 months with the addition of ipatasertib versus 5.6 months with abiraterone monotherapy (stratified HR, 0.84; 95% CI, 0.51-1.37).

In the IPATential150study, the PTEN loss cohort showed a median time to PSA progression of 12.6 months with the ipatasertib add-on versus 7.6 month with abiraterone alone (stratified HR, 0.69; 95% CI, 0.55-0.67; P = .0013). The ITT population showed a median time to PSA progression of 12.9 months in the ipatasertib plus abiraterone arm versus 6.4 months in the abiraterone monotherapy arm (stratified HR, 0.73; 95% CI, 0.62-0.85; P = .0001).

The difference in time to pain progression among patients with the PTEN loss cohort was demonstrated with a stratified HR of 0.77 (95% CI, 0.56-1.04). In the ITT population, the difference was shown with a stratified HR of 0.87 (95% CI, 0.70-1.08).

The study also looked at a next-generation-defined PTEN loss population aside from those defined with IHC. In this group, the rPFS was 19.1 months (95% CI, 13.9 -not evaluable) with the combination of ipatasertib and abiraterone compared with 14.2 months (95% CI, 10.9-18.7) with abiraterone alone (HR, 0.65; 95% CI, 0.45-0.95; P =.0206).

Patients in both the PTEN loss and ITT populations of the study received treatment for a similar amount of time, which ranged from 11.1 months to 14.0 months. The incidence of adverse events (AEs) did not appear to be impacted by treatment duration. Overall, 99.5% of the ipatasertib plus abiraterone arm experienced AEs compared with 91.5% of the patients treated with abiraterone alone. Of the AEs that occurred, 70.1% of those in the ipatasertib-containing arm were grade 3-5 and 4.4% were grade 5. In the monotherapy arm, 39.0% of the AEs were grade 3-5 and 3.7% were grade 5.

The occurrence of AEs led to treatment discontinuation in 21.1% of the ipatasertib/ abiraterone versus 5.1% of the monotherapy arm, and dose reductions in 39.9% versus 6.2%, respectively. AEs led to dose interruptions in 57.9% of the ipatasertib plus abiraterone arm compared with 22.95 of the abiraterone alone arm, and treatment with abiraterone was discontinued due to AEs in 8.5% of the combination arm versus 4.0% of the monotherapy arm.

Grade 3/4 AEs were seen in at least 2% of the study population. The most common in the combination arm versus the single-agent arm were rash/rash maculopapular, diarrhea, hypoglycemia, alanine aminotransferase increased, aspartate aminotransferase increased, and dehydration.

de Bono noted during his presentation that the combination of ipatasertib plus abiraterone led to increased toxicity, but this findings align with other clinical trials, as did the amount of dose changes required to limit AEs in patients. He also recommended the use of prophylactic loperamide and antihistamines to manage AEs like diarrhea and cutaneous events.

The study data for the overall survival and objective response rates continue to be calculated, as they are immature. Further follow-up is ongoing.

IPATential150 enrolled patients with asymptomatic or mildly symptomatic mCRPC who were not previously treated for the disease. Patients were stratified by tumor PTEN loss by IHC, prior docetaxel in the hematopoietic stem/progenitor cell setting, progression by PSA only, the presence of liver and lung metastases, and geographic region.

Baseline characteristics showed that the PTEN loss by IHC population had a median age of 70 years (range, 48-92) in the combination arm versus 70 years (range, 47-87) in the monotherapy arm. The ITT population showed a median age of 69 years (range, 47-93) in the combination group versus 70 years (range, 44-90) in the monotherapy group. The study included patients who identified as White or Asian, with the majority being White.

In terms of prior taxane-based therapy, more prior treatment was observed in the PTEN loss population compared with the ITT population, however, no significant difference was observed between the treatment arms. The same was true for PSA-only progression factor.

Metastatic sites in study patients included lung or liver, bone, lymph nodes, and other. A larger proportion of patients in the ITT population had metastatic disease than those in the PTEN loss population. Still, no significant difference in the proportion of metastases was observed between the treatment arms.

The conclusion drawn from this research was that the combination of AR inhibition with AKT inhibition is superior to AR blockade in terms of clinical outcomes in the subset of patients with mCRPC who had PTEN loss.

_References:

_{1. de Bono J, Baracarda S, Sternberg CN, et al. Combinatorial targeting of AR and AKT with abiraterone and ipatasertib for mCRPC with and without PTEN loss: The Ipatential150 phase 3 trial. Presented at 27th Annual PCF Scientific Retreat Virtual Poster Session; Oct 20-23, 2020.}

_{2. de 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. Clin Cancer Res. 2009;25(3):928–936. doi: 10.1158/1078-0432.CCR-18-0981}