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Neoadjuvant hormonal therapy before radical prostatectomy in high-risk prostate cancer

Subjects

Abstract

Patients with high-risk prostate cancer treated with curative intent are at an increased risk of biochemical recurrence, metastatic progression and cancer-related death compared with patients treated for low-risk or intermediate-risk disease. Thus, these patients often need multimodal therapy to achieve complete disease control. Over the past two decades, multiple studies on the use of neoadjuvant treatment have been performed using conventional androgen deprivation therapy, which comprises luteinizing hormone-releasing hormone agonists or antagonists and/or first-line anti-androgens. However, despite results from these studies demonstrating a reduction in positive surgical margins and tumour volume, no benefit has been observed in hard oncological end points, such as cancer-related death. The introduction of potent androgen receptor signalling inhibitors (ARSIs), such as abiraterone, apalutamide, enzalutamide and darolutamide, has led to a renewed interest in using neoadjuvant hormonal treatment in high-risk prostate cancer. The addition of ARSIs to androgen deprivation therapy has demonstrated substantial survival benefits in the metastatic castration-resistant, non-metastatic castration-resistant and metastatic hormone-sensitive settings. Intuitively, a similar survival effect can be expected when applying ARSIs as a neoadjuvant strategy in high-risk prostate cancer. Most studies on neoadjuvant ARSIs use a pathological end point as a surrogate for long-term oncological outcome. However, no consensus yet exists regarding the ideal definition of pathological response following neoadjuvant hormonal therapy and pathologists might encounter difficulties in determining pathological response in hormonally treated prostate specimens. The neoadjuvant setting also provides opportunities to gain insight into resistance mechanisms against neoadjuvant hormonal therapy and, consequently, to guide personalized therapy.

Key points

  • Patients with high-risk prostate cancer are at an increased risk of biochemical recurrence, metastatic progression and cancer-related death following primary treatment compared with patients with low-risk or intermediate-risk disease.

  • Multiple studies on neoadjuvant treatment using conventional androgen deprivation therapy before radical prostatectomy have reported reduced positive surgical margins and tumour volume but no benefits in hard oncological end points.

  • Androgen receptor signalling inhibitors have demonstrated substantial survival benefits in metastatic and non-metastatic castration-resistant and metastatic hormone-sensitive prostate cancer.

  • The importance of pathological response following neoadjuvant hormonal therapy is unclear, and the effect of hormonal therapy on the prostate tissue renders pathological assessment difficult.

  • The presence of castration-resistant prostate cancer cells in early disease stages or rapid therapy-induced resistance might be responsible for the low proportion of pathological complete response (10%) in neoadjuvant androgen receptor signalling inhibitor studies.

  • Longitudinal imaging could help to identify early responders by assessing the effect of neoadjuvant hormonal therapy on the local tumour and possible micrometastases.

  • Ongoing and future neoadjuvant studies should include translational end points to identify early resistance mechanisms and to develop novel biomarkers, enabling personalized neoadjuvant hormonal treatment for patients with high-risk prostate cancer.

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Fig. 1: Steroidogenesis and mechanisms of hormonal therapies.
Fig. 2: Difficulties pathologists might encounter when determining minimal residual disease defined as remaining maximal tumour diameter <5 mm following neoadjuvant treatment.
Fig. 3: Histological features following neoadjuvant hormonal therapy.
Fig. 4: Possible resistance mechanisms to neoadjuvant hormone-based therapy.
Fig. 5: Different phases in the development of predictive biomarkers in the neoadjuvant setting.
Fig. 6: Future perspectives of biomarker-guided studies.

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Acknowledgements

G.D. is a PhD fellow of the Research Foundation Flanders (FWO). W.D. is a recipient of the Emmanuel van der Schueren scholarship of “Kom Op Tegen Kanker”. W.E. is a Senior Clinical Investigator of the FWO. S.J. is a Senior Clinical Investigator of the FWO. This work was supported by the ‘Jozef De Wever Fonds voor prostaatkankerpreventie’ of the KU Leuven.

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G.D., W.D., F.C. and S.J. researched data for the article. G.D., W.D., G.D.M., M.B., F.C. and S.J. made a substantial contribution to discussion of content. G.D., W.D., M.B., F.C. and S.J. wrote the article. G.D., W.D., G.D.M., T.G., L.M., D.M., H.V.P., C.B., W.E., F.C. and S.J. reviewed and/or edited the manuscript before submission.

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Correspondence to Gaëtan Devos.

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Nature Reviews Urology thanks W. Dahut, E. Klein and J. Parsons for their contribution to the peer review of this work.

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Glossary

Biochemical recurrence

(BCR). Rising PSA following treatment with curative intent (surgery or radiotherapy) for localized prostate cancer. Often defined as a (confirmed) rise in PSA to 0.2 ng/ml or more following radical prostatectomy, or a rise of 2 ng/ml or more above the PSA nadir after radiation therapy for localized prostate cancer.

Hotspot mutations

Gain-of-function mutations.

Poly(ADP-ribose) polymerase (PARP) inhibitor

A family of nuclear proteins involved in the single-strand break DNA repair pathway. Inhibition of poly(ADP-ribose) polymerase (PARP) is effective in men with mutations of the homologous recombination DNA repair pathway (such as BRCA1 and BRCA2), which promotes DNA double-strand break repair. PARP inhibition blocks single-strand break repair that evolves in a double-strand break, which cannot be repaired because of a deficiency of the homologous recombination DNA repair pathway.

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Devos, G., Devlies, W., De Meerleer, G. et al. Neoadjuvant hormonal therapy before radical prostatectomy in high-risk prostate cancer. Nat Rev Urol 18, 739–762 (2021). https://doi.org/10.1038/s41585-021-00514-9

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