Efficacy and Safety of Combination AKT and Androgen Receptor Signaling Inhibition in Metastatic Castration-Resistant Prostate Cancer: Systematic Review and Meta-Analysis

Abstract

Background: Metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis with current treatment options including chemotherapy and androgen receptor signaling inhibitor (ARSI) medications. Poly-ADP ribose polymerase (PARP) inhibitors alone and in combination with ARSI has recently been incorporated in management for mCRPC deficient in BRCA1/2 genes. However, downregulating androgen-receptor signaling using ARSIs can upregulate the PI3K/AKT/mTOR pathway, promoting tumor cell survival. This creates a rationale for co-targeting both these pathways. This systematic review aimed to investigate AKT inhibitors and ARSI combination therapy.

Methods: EMBASE, MEDLINE, and Scopus were searched from database inception to July 2023. Primary outcomes included objective response rate (ORR), prostate-specific antigen (PSA) response rate, adverse events (AEs), overall survival (OS), and radiographic progression-free survival (rPFS). Quality was assessed using the risk of bias tool (ROB2) and certainty of evidence with GRADE.

Results: Six clinical trials with 3 Phase I, 1 Phase II, 1 Phase III were included with 771 patients and a median age ranging from 67 years to 70 years. The pooled ORR was 30% (n = 5 studies, 95% CI, 3%-84%) and PSA response rate was 43% (n = 5 studies, 95% CI, 15%-77%). The median duration of rPFS ranged from 8.2 to 19.2 months in the intervention compared with 6.4 to 16.6 months in the placebo group. A 16% reduction in radiographic progression or death was reported in patients receiving dual therapy compared with those receiving placebo. This reduction was greater by PTEN-loss status, ranging from 23% to 61%. The median OS ranged from 15.6 to 18.9 months. No significant difference was reported in survival relative to placebo. 98.8% (767/776) of patients experienced AEs of any grade, with GRADE ≥3 AEs occurring in 65.9% (512/776) of patients. The most common AE and GRADE ≥3 AEs were diarrhoea (pooled prevalence = 70%, 95% CI, 57%-81%), and hyperglycaemia (pooled prevalence = 12%, 95% CI, 6%-20%), respectively.

Conclusion: Combined therapy reduced the risk of rPFS, with the response higher in PTEN-loss subgroup, with a modest but not significant increase in OS. Our AE estimates showed consistency with other studies. AEs of any grade were common with the majority experiencing at least 1 AE. (PROSPERO Registration Number: CRD420202352583).

Keywords: AKT inhibitor; Androgen receptor signalling inhibitor; Combination therapy; Meta analysis; Metastatic castration resistant prostate cancer.