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

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)