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  • Review Article
  • Published:

Drug development for noncastrate prostate cancer in a changed therapeutic landscape

Nature Reviews Clinical Oncology volume 15, pages 168–182 (2018)Cite this article

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An Erratum to this article was published on 08 November 2017

This article has been updated

Key Points

  • The increasing number of both approved and experimental therapies available mandates the use of new trial designs for patients with noncastrate prostate cancer, which provide expedited readouts of efficacy

  • Trials based on time-to-event end points, such as progression to metastatic disease and overall survival, require large numbers of patients with long follow-up durations, and might provide inconclusive results owing to use of post-protocol interventions

  • To accelerate progress, a multi-arm, multistage, multimodality trial platform involving delivery of systemic therapy, radiotherapy to detectable metastases, and radical surgery was developed that enables new arms to be added at any time

  • The objective is to eliminate all disease using binary quantitative end points that occur early and solely reflect the effects of treatment, such as pathological complete response and undetectable serum prostate-specific antigen levels after testosterone recovery

Abstract

The unprecedented progress in the treatment of metastatic castration-resistant prostate cancer is only beginning to be realized in patients with noncastrate disease. This slow progress in part reflects the use of trial objectives focused on time-to-event end points, such as time to metastasis and overall survival, which require long follow-up durations and large sample sizes, and has been further delayed by the use of approved therapies that are effective at the time of progression. Our central hypotheses are that progress can be accelerated, and that outcomes can be improved by shifting trial objectives to response measures occurring early that solely reflect the effects of the treatment. To test these hypotheses, a continuously enrolling multi-arm, multi-stage randomized trial design, analogous to that used in the STAMPEDE trial, has been developed. Eligibility is focused on patients with incurable disease or those with a high risk of death with any form of monotherapy alone. The primary objective is to eliminate all disease using a multimodality treatment strategy. End points include pathological complete response and an undetectable level of serum prostate-specific antigen, with recovery of serum testosterone levels. Both are binary, objective, and provide an early, quantitative indication of efficacy.

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Figure 1: Percentage of patients with an undetectable serum PSA level following multimodality therapy.
Figure 2: Multimodality treatment schema for multiarm, multistage trials in patients with advanced-stage prostate cancer.
Figure 3: Frequency of genetic alterations in different disease states.

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Change history

  • 08 November 2017

    In the version of this Review published online ahead of print, The Acknowledgements section in the online and PDF versions of this manuscript originally contained the text "The authors gratefully acknowledge financial support from the Prostate Cancer Clinical Trials Consortium of the Prostate Cancer Foundation, and a SPORE Center Grant to the Sidney Kimmel Center for Prostate and Urologic Cancers." This was incorrect and has been corrected to "The authors gratefully acknowledge financial support from the Department of Defense Prostate Cancer Research Program (PC121111 and PC131984), the NIH/NCI (Cancer Center Support Grant P30-CA008748, P50-CA92629 SPORE in Prostate Cancer), the Prostate Cancer Foundation, and the Sidney Kimmel Center for Prostate and Urologic Cancers” in the online and PDF versions of this manuscript.

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Acknowledgements

The authors gratefully acknowledge financial support from the Department of Defense Prostate Cancer Research Program (PC121111 and PC131984), the NIH/NCI (Cancer Center Support Grant P30-CA008748, P50-CA92629 SPORE in Prostate Cancer), the Prostate Cancer Foundation, and the Sidney Kimmel Center for Prostate and Urologic Cancers.

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Authors and Affiliations

  1. Department of Medicine, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Min Yuen Teo & Howard I. Scher

  2. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Matthew J. O'Shaughnessy

  3. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Sean M. McBride

  4. Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10065, New York, USA

    Herbert A. Vargas

  5. Weill Cornell Medical College, 1300 York Avenue, New York, 10065, New York, USA

    Howard I. Scher

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  1. Min Yuen Teo
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All authors contributed to all aspects of the preparation of this manuscript.

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Correspondence to Howard I. Scher.

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Competing interests

H.I.S. declares that he is a member of the board of directors of Asterias Biotherapeutics, has served as a compensated consultant of Blue Earth Diagnostics, Sanofi Aventis, and WCG Oncology, and has served as an uncompensated consultant of Ferring Pharmaceuticals, Janssen Research & Development, LLC and Medivation. M.Y.T., M.J.O., S.M.M. and H.A.V. declare no competing interests.

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Teo, M., O'Shaughnessy, M., McBride, S. et al. Drug development for noncastrate prostate cancer in a changed therapeutic landscape. Nat Rev Clin Oncol 15, 168–182 (2018). https://doi.org/10.1038/nrclinonc.2017.160

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