(1) Background: Several phase II studies, including randomized controlled trials (RCTs), assessed the efficacy of adding androgen receptor signaling inhibitors (ARSIs) to androgen deprivation therapy (ADT) as a neoadjuvant treatment in patients treated with radical prostatectomy (RP) for prostate cancer (PCa). Summarizing the early results of these studies could help in designing phase III trials and patient counseling. (2) Methods: We queried three databases in January 2023 for studies that included PCa patients treated with neoadjuvant ARSI-based combination therapy before RP. The outcomes of interest were oncologic outcomes and pathologic responses, such as pathologic complete response (pCR) and minimal residual disease (MRD). (3) Results: Overall, twenty studies (eight RCTs) were included in this systematic review. Compared to ADT or ARSI alone, ARSI + ADT was associated with higher pCR and MRD rates; this effect was less evident when adding a second ARSI or chemotherapy. Nevertheless, ARSI + ADT resulted in relatively low pCR rates (0-13%) with a high proportion of ypT3 (48-90%) in the resected specimen. PTEN loss, ERG positive, or intraductal carcinoma seem to be associated with worse pathologic response. One study that adjusted for the effects of possible confounders reported that neoadjuvant ARSI + ADT improved time to biochemical recurrence and metastasis-free survival compared to RP alone. (4) Conclusions: Neoadjuvant ARSI + ADT combination therapy results in improved pathologic response compared to either alone or none in patients with non-metastatic advanced PCa. Ongoing phase III RCTs with long-term oncologic outcomes, as well as biomarker-guided studies, will clarify the indication, oncologic benefits, and adverse events of ARSI + ADT in patients with clinically and biologically aggressive PCa.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal QC H2X 0A9 Canada

Clinic of Urology and Urological Oncology Jagiellonian University 30 688 Krakow Poland

Department of Urology 2nd Faculty of Medicine Charles University 15006 Prague Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna Wahringer Gurtel 43 18 20 1090 Vienna Austria

Department of Urology King Fahad Specialist Hospital Dammam 32253 Saudi Arabia

Department of Urology Medical University of Silesia 41 800 Zabrze Poland

Department of Urology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama 700 8530 Japan

Department of Urology The Jikei University School of Medicine Tokyo 105 8461 Japan

Department of Urology University Medical Center Hamburg Eppendorf 20251 Hamburg Germany

Department of Urology University of Texas Southwestern Medical Center Dallas TX 75390 USA

Department of Urology Weill Cornell Medical College New York NY 10021 USA

Division of Urology Department of Special Surgery The University of Jordan Amman 19328 Jordan

Institute for Urology and Reproductive Health Sechenov University 119435 Moscow Russia

Karl Landsteiner Institute of Urology and Andrology 1090 Vienna Austria

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