Citation: Fiorica, F.; Buttigliero, C.; Grigolato, D.; Muraro, M.; Turco, F.; Munoz, F.; Tucci, M. Addition of New Androgen Receptor Pathway Inhibitors to Docetaxel and Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and Metanalysis. Curr. Oncol. 2022, 29, 9511–9524. https://doi.org/ 10.3390/curroncol29120747 Received: 12 September 2022 Accepted: 1 December 2022 Published: 4 December 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Systematic Review Addition of New Androgen Receptor Pathway Inhibitors to Docetaxel and Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and Metanalysis Francesco Fiorica 1, * , Consuelo Buttigliero 2 , Daniela Grigolato 1 , Marco Muraro 1 , Fabio Turco 2 , Fernando Munoz 3 and Marcello Tucci 4 1 Department of Radiation Oncology and Nuclear Medicine, AULSS 9 Scaligera, 37045 Verona, Italy 2 Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, 10093 Torino, Italy 3 Radiation Oncology TomoTherapy Center, Hospital of Aosta, 11000 Aosta, Italy 4 Department of Medical Oncology, Cardinal Massaia Hospital, 14100 Asti, Italy * Correspondence: francesco.fiorica@aulss9.veneto.it 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. Keywords: triplet therapy; hormone-sensitive prostate cancer; high volume metastatic disease; de novo metastatic disease; systematic review; metanalysis 1. Introduction Prostate cancer (PC) is the second most frequent cancer diagnosed in men and the fifth leading cause of death worldwide [1]. While, in localized prostate cancer, a person- alized treatment approach according to the patient’s class of risk can allow a cure (active surveillance, prostatectomy, radiotherapy +/- ADT), patients with metastatic prostate cancer are often considered incurable [2]. Prostate cancer arises as an androgen-driven dis- ease, and androgen deprivation therapy (ADT) has been the standard of care in metastatic hormone-sensitive PC (mHSPC) since 1940 [3]. ADT induces a response in more than 90% of patients. Despite the high probability of initial response, after a median time of about 20 months, the disease becomes resistant to ADT, with progression to the castration Curr. Oncol. 2022, 29, 9511–9524. https://doi.org/10.3390/curroncol29120747 https://www.mdpi.com/journal/curroncol