New hormonal agents and integrated strategies for non-metastatic, hormone-sensitive prostate carcinoma: the orphan setting?—a narrative review

Background and Objective: Most of newly diagnosed prostate carcinomas (PCas) present as non-metastatic disease, with approximately 15% of them presenting with characteristics predicting for a high-risk of relapse. Hence, specific focus has to be placed on patients affected by localised or locally advanced disease, whose chances of cure are notably higher than those of patients in advanced settings. With androgen receptor pathway inhibitors (ARPIs) and docetaxel chemotherapy improving treatment efficacy outcomes when compared to traditional androgen deprivation therapy (ADT) in the metastatic disease, clinical trials are currently investigating the activity of ARPI for clinical management of localised or locally advanced prostate patients, with the aim of preventing the cancer from spreading systemically. To provide further insight into the biological and clinical rationale of an early treatment intensification, here we review and enlist promising studies on the treatment of localised, locally advanced, and biochemically relapsed disease. Finally, we briefly review the latest experimental treatments for these early stages—including novel agents and combinations which are believed to shape the future practice. Methods: PubMed and MEDLINE databases were searched for trials focusing on the treatment of localised/locally advanced PCa, and which included the use of second-generation ARPIs. Also, proceedings from major oncology and uro-oncology meetings were screened. Key Content and Findings: Our analysis has not yielded significant results supporting the implementation of second-generation ARPIs in the perioperative or neoadjuvant treatment of localised PCa. However, the data suggest these drugs may offer benefits in the adjuvant setting, following both radical prostatectomy (RP) and primary radiotherapy (RT). Conclusions: The design of clinical trials that explore surrogate endpoints like metastasis-free survival (MFS) or employing multi-arm trials with genomic testing could facilitate further advancements in this field, as well as research on combining ARPI treatment with inhibition of other pathways or exploiting the immune response beyond PD-1/CD276.