The clinical rationale for treatment of castration-sensitive prostate cancer (CSPC) with novel hormonal therapy (NHT) or androgen receptor pathway inhibitor is reviewed. A PubMed search was conducted to identify relevant publications on NHTs for CSPC treatment. Level 1 clinical evidence demonstrated that intensification of androgen deprivation therapy (ADT) with NHT prolongs life and improves or maintains quality of life in patients with metastatic CSPC (mCSPC). Despite these results, real-world evidence demonstrated that 47%-88% of patients with mCSPC are treated with single agent ADT. Possible explanations for the underutilization of NHTs include patient characteristics, misperceptions about the overall survival benefit, lack of physician and patient awareness of the magnitude of clinical trial results, physician bias, safety concerns, misconceptions about the magnitude of prostate-specific antigen response needed for patient improvement, and barriers to NHT access. For patients with biochemical recurrence and no evidence of metastatic disease, limited clinical data exist with no consensus on an effective treatment strategy. Therefore, treatment strategies are developed using patient risk stratification according to clinicopathological characteristics, genomics, and next-generation imaging. Patients with high-risk biochemical recurrence may benefit from the early initiation of NHT based on outcomes from the phase III EMBARK trial. Lifestyle management is also an important aspect of treatment for CSPC, helping to mitigate the side effects of hormonal treatment and ensuring patients can maintain treatment while optimizing quality of life. In conclusion, to improve outcomes in patients with mCSPC, it is important to implement solutions addressing the barriers to underutilization of treatment intensification., Competing Interests: Disclosures The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Stephen J. Freedland – consultant to Astellas Pharma, AstraZeneca, Bayer, Exact Sciences, Johnson & Johnson Innovative Medicine (formerly Janssen Biotech), Merck, Sumitomo Pharma America, Inc. (formerly Myovant Sciences), Pfizer, and Sanofi. Daniel J. George – reported receiving grants from Acerta Pharmaceuticals; other from American Association for Cancer Research; grants and personal fees from Astellas Pharma; personal fees from AstraZeneca; personal fees from Axess Oncology; grants, personal fees, and nonfinancial support from Bayer H/C Pharmaceuticals; grants and personal fees from Bristol Myers Squibb; grants from Calithera; grants from Capio Biosciences; grants from EMD Serono; grants, personal fees, and nonfinancial support from Exelixis, Inc.; personal fees from Flatiron; personal fees from Ipsen; grants and personal fees from Johnson & Johnson Innovative Medicine (formerly Janssen Biotech); personal fees from Merck, Sharp & Dohme; personal fees from Michael J Hennessey Associates; personal fees from Millennium Medical Publishing; personal fees from Modra Pharmaceuticals B.V.; personal fees from Sumitomo Pharma America, Inc. (formerly Myovant Sciences); personal fees from NCI Genitourinary; personal fees from Nektar Therapeutics; grants and personal fees from Novartis; personal fees from Physician Education Resource; grants and personal fees from Pfizer Inc.; grants, personal fees, and nonfinancial support from Sanofi; personal fees from UroGPO; personal fees and nonfinancial support from UroToday; personal fees from Vizuri Health Sciences; and personal fees from Platform Q, outside the submitted work. Alicia K. Morgans – reports honoraria from Genentech, Johnson & Johnson Innovative Medicine (formerly Janssen), Sanofi, AstraZeneca, Astellas Scientific and Medical Affairs Inc., Astellas Pharma, Johnson & Johnson Innovative Medicine (formerly Janssen), Bayer, Clovis Oncology, Sumitomo Pharma America, Inc. (formerly Myovant Sciences), Advanced Accelerator Applications, Exelixis, Pfizer, and Merck; consulting or advisory roles with AstraZeneca, Sanofi, Bayer, Astellas Pharma, Johnson & Johnson Innovative Medicine (formerly Janssen), Advanced Accelerator Applications, Sumitomo Pharma America, Inc. (formerly Myovant Sciences), Blue Earth Diagnostics, Exelixis, Novartis, Myriad Genetics, Lantheus Medical Imaging, and Merck; research funding from Bayer, Seattle Genetics/Astellas, Genentech, AstraZeneca, Astellas Scientific and Medical Affairs Inc., Dendreon, Sanofi, and Sumitomo Pharma America, Inc. (formerly Myovant Sciences); and travel, accommodation, and expenses from Sanofi. Cora N. Sternberg – Served as a consultant for Janssen-Cilag, Astellas Pharma, Sanofi–Genzyme, Novartis, Bayer, Pfizer Inc., Merck, Merck Sharp & Dohme, AstraZeneca, Gilead (formerly Immunomedics), Johnson & Johnson Innovative Medicine (formerly Janssen), Eli Lilly, Foundation Medicine, UroToday, and Medscape; and has received prior institutional funding from Johnson & Johnson Innovative Medicine (formerly Cougar Biotechnology and Janssen), Pfizer (formerly Medivation), Clovis Oncology, and Roche-Genentech., (Copyright © 2024. Published by Elsevier Inc.)