Beyond the Abstract - Old issues and new perspectives on prostate cancer hormonal therapy: The molecular substratum, by Leonardo Oliveira Reis, MD., MSc., PhD

BERKELEY, CA ( - Although the AR (androgen receptor) is the major therapeutic target of prostate cancer, there are currently no clinical studies available in which the AR status was considered in the study design.

Furthermore, to date, even with better understanding of the molecular pathways behind CRPC (castration resistant prostate cancer), no study of secondary hormonal treatment with a strong methodology has shown a benefit in terms of survival, but most trials have been smaller and heavily biased for patient heterogeneity. Because patients with CRPC are a very diverse group, management of these patients represents a unique challenge.

Managing strategies should be targeted toward the individual patient, and several issues will guide therapeutic choices: castration status, previous therapies, their response and duration, current pace of progression, manifestations and symptoms, the disease stage, recurrence, metastasis type (bone, lymphatic, liver, other), uni- or multifocal, comorbidities, and organ functions.

Further investigation is required to determine how to best deliver hormonal therapy and how to combine hormonal agents in multimodal treatment strategies to prolong survival and improve quality of life. Finally, depleting the AR-signal redundancy would require an annihilation approach where an environment of collateral androgen depletion is combined with ligand-independent interventions.

While the translation of current pathogenetic concepts into potential therapeutic applications remains highly challenging, early detection, prevention, and treatment optimization of a blend of numerous pathways that enhance and widen the function of the AR, added to AR bypass involved in CRPC, may provide another strategy to improve survival in patients prone to castration failure. In this scenario of current understandings of the molecular milieu involved in the CRPC, the biggest impact on mortality is likely to come from multimodal combination therapies targeting multiple steps in androgen synthesis, which are promising in current clinical practice.

For example, an annihilation approach may include a combination of an LHRH agonist or castration, 5-alpha-reductase inhibitor, a second-generation antiandrogen, a CYP17A1 inhibitor, and an AR degrader.

Written by:
Leonardo Oliveira Reis, MD., MSc., PhD.,1 as part of Beyond the Abstract on This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

1Assistant Professor, Division of Urologic Oncology, School of Medical Sciences, University of Campinas, UNICAMP, Brazil

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