Addition of New Androgen Receptor Pathway Inhibitors to Docetaxel and Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and Metanalysis

Abstract

In recent years, significant changes have occurred in metastatic hormone-sensitive prostate cancer (mHSPC) management, where docetaxel and new androgen receptor pathway inhibitors (ARPI) have been shown to improve overall survival (OS) compared to androgen deprivation therapy (ADT). Recent data could once again radically change mHSPC treatment. PEACE-1 and ARASENS trials demonstrated a survival benefit of the addition of ARPI to docetaxel and ADT combination (triplet therapy), compared to docetaxel and ADT. With multiple options to choose from, it is crucial to identify the patients who would benefit most from triplet therapy. In this meta-analysis, we evaluated the activity of the triplet therapy versus docetaxel plus ADT in mHSPC. A systematic review of PubMed/Medline, Embase, and the proceedings of major international meetings was performed. Five RCTs fulfilled the inclusion criteria. PEACE-1 and ARASENS studies reported disease-free survival (DFS) and OS. Post hoc analysis of three other trials evaluated the combination of ARPI, docetaxel and ADT. Globally, 2538 patients were included (1270 triplet therapy; 1268 docetaxel + ADT). Triplet therapy was associated with improved OS (hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.66–0.83, p < 0.00001). A statistically significant benefit was shown in high-volume mHSPC patients (HR 0.76; 95% CI 0.59–0.97, p = 0.03) and in patients with de novo metastatic disease (HR 0.73; 95% CI, 0.64–0.82, p < 0.00001). The addition of ARPI to standard therapy was associated with DFS improvement (HR 0.41; 95% CI, 0.35–0.49, p < 0.00001). This metanalysis shows a significant OS benefit from concomitant administration of ARPI, docetaxel and ADT in high volume and de novo mHSPC.

Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer

“…Similarly, the SU2C dataset confirmed our finding that pharmacological inhibition of AR using ARSIs does not inhibit HMMR gene expression, as HMMR remained unchanged by ARSI treatment in CRPC tumours compared to untreated CRPC (Supplementary Figure 1g ) [ 24 ]. Given the increasing use of ARSIs in combination with ADT clinically [ 25 ], we evaluated HMMR expression in response to enzalutamide under androgen-deprived conditions. To simulate androgen deprivation in vitro, androgen-sensitive LNCaP and VCAP cells and androgen-independent V16D cells were androgen-starved for three days.…”

Advances in Molecular Regulation of Prostate Cancer Cells by Top Natural Products of Malaysia

“…The introduction of a new concept of systemic disease: high-risk or high-volume vs. low-risk and low-volume disease [119] opened a new clinical scenario for sequence therapies using the above-discussed drugs [120,121]. All major clinical associations have reflected these breakthroughs in treatment in updated professional guidelines.…”