Phase II Randomized Study of MK-2206 and Bicalutamide in Prostate Cancer Patients With Rising PSA After Primary...

Area of Science:

• Oncology
• Pharmacology
• Urology

Background:

• Biochemical recurrence (BCR) of prostate cancer (PC) is a significant clinical challenge.
• Combined inhibition of AKT and androgen receptor (AR) pathways may offer enhanced efficacy over AR inhibition alone in BCR.
• This study investigates the potential additive effects of targeting both pathways in high-risk BCR patients.

Purpose of the Study:

• To evaluate the efficacy of combined AKT inhibitor MK-2206 and bicalutamide (Bic) versus bicalutamide alone in high-risk BCR patients.
• To assess whether AKT inhibition influences PSA levels, indicating AR activation, prior to combination therapy.
• To identify patient subgroups that may benefit from combined AKT and AR inhibition.

Main Methods:

• A phase study (E2809) enrolled 108 high-risk BCR patients randomized 1:1 to two arms.
• Arm B received MK-2206 plus bicalutamide, while Arm A received observation followed by bicalutamide.
• The study involved a pre-treatment phase with MK-2206 to assess PSA changes, followed by combination therapy cycles, with endpoints at cycles 8 and 14.

Main Results:

• The pre-treatment phase showed a significantly higher PSA rise in the MK-2206 arm (70%) compared to observation (32%), suggesting AR activation.
• While initial PSA response rates were similar, at a later time point (EP2), progressive disease (PD) was significantly lower in the combined MK-2206/bicalutamide arm (11% vs 36%).
• A subgroup of patients with pre-treatment PSA rise (≥25%) showed a marked benefit from combined therapy, with significantly less PD (27% vs 73% in the bicalutamide-only arm).

Conclusions:

• Combined MK-2206 and bicalutamide therapy demonstrated a potential for improved outcomes in a subgroup of high-risk BCR patients.
• This benefit appears attributable to targeting crosstalk AR activation secondary to AKT inhibition in specific patient populations.
• Toxicity of MK-2206, particularly skin reactions, may limit the tolerance for sustained combined AKT-AR inhibition.