How the Management of Biochemical Recurrence in Prostate Cancer Will Be Modified by the Concept of Anticipation and Incrementation of Therapy

Simple Summary The risk of early progression to metastatic disease in the event of biochemical recurrence (BCR) after primary treatment for prostate cancer (PC) is extremely variable. PSA-doubling time (DT) is the best parameter currently available to define patients who are at a higher risk of progression, but a single temporal parameter is not sufficient to describe the heterogeneity of this condition. A real precision medicine approach is strongly suggested to offer tailored management to patients with biochemical relapse. At present, patients with low-risk BCR should be offered active observation, while patients with high-risk BCR are likely to benefit from early systemic therapy. Results from the EMBARK study are likely to impact how physicians choose to manage high-risk BCR. The introduction of the concept of anticipation and intensification of treatment through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy in this indolent but crucial phase is the main innovation of the study. The aim of this review is to provide a comprehensive understanding of the definition, classification, diagnosis, and treatment modalities of BCR, with a focus on the latest innovations and ongoing trials in the management of high-risk BCR.Abstract Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification into low- and high-risk cases for early progression in metastatic disease is necessary. At present, PSA-DT represents the best parameter to define low- and high-risk BCR PC, but real precision medicine is strongly suggested to define tailored management for patients with BCR. Before defining management, it is necessary to exclude the presence of low-volume metastasis associated with PSA progression using new-generation imaging, preferably with PSMA PET/CT. Low-risk BCR cases should be actively observed without early systemic therapies. Early treatment of low-risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such as the development of castration resistance before the appearance of metastases (non-metastatic castration-resistant PC). Patients with high-risk BCR benefit from early systemic therapy. Even with overall survival (OS) as the primary treatment endpoint, metastasis-free survival (MFS) should be used as a surrogate endpoint in clinical trials, especially in long survival stages of the disease. The EMBARK study has greatly influenced the management of high-risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy. In high-risk (PSA-DT <= 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining an unchanged quality of life in the asymptomatic phase of the disease. The possibility of using ARSIs alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than with the intensification of the combination therapy. Continued use versus discontinuation of enzalutamide plus leuprolide intensified therapy upon reaching undetectable PSA levels needs to be better defined with further analysis. Real-world analysis must verify the significant results obtained in the context of a phase 3 study.