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Treatment and trials in non-metastatic castration-resistant prostate cancer

Nature Reviews Urology volume 18, pages 433–442 (2021)Cite this article

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Abstract

Metastatic prostate cancer is associated with considerable morbidity and mortality. Standard treatment for non-metastatic prostate cancer, to prevent metastatic progression, is androgen deprivation therapy (ADT); however, many patients will eventually develop castration-resistant prostate cancer (CRPC), which can prove challenging to treat. Between the stages of non-metastatic androgen-sensitive disease and metastatic CRPC is an intermediate disease state that has been termed non-metastatic CRPC (nmCRPC), which is a heterogeneous, man-made disease stage that occurs after a patient who has no radiological evidence of metastasis shows evidence of cancer progression even after ADT. Awareness of nmCRPC has risen owing to an increased use of ADT and its eventual failure. Men with nmCRPC are at a high risk of progression to mCRPC, with historically few options to halt this process. However, in the past two decades, multiple therapies have been investigated for the treatment of nmCRPC, including endothelin receptor antagonists and bone-targeted therapies, but none has changed the standard of care. In the past decade, the efficacy of androgen receptor pathway-targeting modalities has been investigated. Three novel nonsteroidal antiandrogen agents for treating high-risk nmCRPC have been investigated; the PROSPER, SPARTAN and ARAMIS trials were phase III, randomized, placebo-controlled clinical trials that investigated the efficacy and safety of enzalutamide, apalutamide and darolutamide, respectively. All three therapeutics showed statistically significant improvements in metastasis-free survival, progression to antineoplastic therapy was lengthened and at final analysis, overall survival was significantly improved. The comparative efficacy and safety of all three agents has not yet been investigated in a comprehensive clinical trial, but approval of these medications by the FDA and other regulatory agencies means that providers now have three effective therapeutic options to augment ADT for patients with nmCRPC.

Key points

  • Non-metastatic castration-resistant prostate cancer (nmCRPC) is a heterogeneous disease classification. This disease stage occurs after a patient with prostate cancer who has no radiological evidence of metastasis shows evidence of cancer progression even after androgen deprivation therapy.

  • Multiple therapies have been investigated for treating nmCRPC, including endothelin receptor antagonists and bone-targeted therapies. Within the past decade, the efficacy of androgen receptor pathway-targeting modalities has been investigated.

  • Three phase III, randomized, placebo-controlled, clinical trials (PROSPER, SPARTAN and ARAMIS) have shown significant metastasis-free survival and overall survival benefits of enzalutamide, apalutamide and darolutamide, respectively.

  • These novel nonsteroidal antiandrogen agents have been approved by governmental agencies, such as the FDA, for nmCRPC, and apalutamide and enzalutamide have been included in international guidelines, such as those from the AUA and EAU.

  • To our knowledge, no head-to-head comparison of all three therapeutic agents exists to compare their efficacy and safety; however, all three have shown comparable efficacy in separate trials.

  • Patient selection can be made through shared decision-making between patients and physicians based on differing adverse effect profiles and other differing parameters between the three therapeutics.

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Fig. 1: Patient selection and treatment options for high-risk non-metastatic castration-resistant prostate cancer.

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  1. Yale University, School of Medicine, New Haven, CT, USA

    Soum D. Lokeshwar

  2. Division of Urology, Department of Surgery, Augusta University – Medical College of Georgia, Augusta, GA, USA

    Zachary Klaassen

  3. Georgia Cancer Center, Augusta, GA, USA

    Zachary Klaassen

  4. Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, QC, Canada

    Fred Saad

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Lokeshwar, S.D., Klaassen, Z. & Saad, F. Treatment and trials in non-metastatic castration-resistant prostate cancer. Nat Rev Urol 18, 433–442 (2021). https://doi.org/10.1038/s41585-021-00470-4

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