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Bipolar androgen therapy plus olaparib in men with metastatic castration-resistant prostate cancer

Prostate Cancer and Prostatic Diseases volume 26, pages 194–200 (2023)Cite this article

Subjects

Abstract

Background

Bipolar androgen therapy (BAT) results in rapid fluctuation of testosterone (T) between near-castrate and supraphysiological levels and has shown promise in metastatic castration-resistant prostate cancer (mCRPC). Its clinical effects may be mediated through induction of DNA damage, and preclinical studies suggest synergy with PARP inhibitors.

Patients and methods

This was a single-center, Phase II trial testing olaparib plus BAT (T cypionate/enanthate 400 mg every 28 days) with ongoing androgen deprivation. Planned recruitment was 30 subjects (equal proportions with/without homologous recombination repair [HRR] gene mutations) with mCRPC post abiraterone and/or enzalutamide. The primary objective was to determine PSA50 response (PSA decline ≥50% from baseline) rate at 12-weeks. The primary analysis utilized the entire (intent-to-treat [ITT]) cohort, with those dropping out early counted as non-responders. Secondary/exploratory analyses were in those treated beyond 12-weeks (response-evaluable cohort).

Results

Thirty-six patients enrolled and 6 discontinued prior to response assessment. In the ITT cohort, PSA50 response rate at 12-weeks was 11/36 (31%; 95% CI 17–48%), and 16/36 (44%, 95% CI 28–62%) had a PSA50 response at any time on-study. After a median follow-up of 19 months, the median clinical/radiographic progression-free survival in the ITT cohort was 13.0 months (95% CI 7–17). Clinical outcomes were similar regardless of HRR gene mutational status.

Conclusions

BAT plus olaparib is associated with high response rates and long PFS. Clinical benefit was observed regardless of HRR gene mutational status.

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Fig. 1: PSA and radiographic response waterfall plots.
Fig. 2: PSA progression-free survival (PSA PFS), clinical/radiographic PFS, and overall survival (OS).
Fig. 3: Associations between functional HRR deficiency scores and maximum PSA50 response.
Fig. 4: Associations between clinical outcomes and baseline PSA values.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the paper and its Supplementary Materials.

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Acknowledgements

This study was supported by a research grant from AstraZeneca. MTS was supported by US DOD Award W81XWH-16-1-0484 and a Prostate Cancer Foundation Young Investigator Award. RG was supported by NIH/NCI grants P50 CA097186 and R50 CA221836. HHC and PSN were supported by NIH/NCI Cancer Center Support Grant P30 CA015704. MCH was supported by the US DOD Awards W81XWH-20-1-0111 and W81XWH-21-1-0229, Grant 2021184 from the Doris Duke Charitable, and the V Foundation. NDS was supported by a Prostate Cancer Foundation Young Investigator Award. PSN was supported by NIH/NCI grants P50 CA097186, 5P01 CA163227, R01CA266452-01 and PC200262.

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Authors and Affiliations

  1. Department of Medicine, University of Washington, Seattle, WA, USA

    Michael T. Schweizer, Todd Yezefski, Heather H. Cheng, Elahe Mostaghel, Katie Nega, Petros Grivas, Andrew Hsieh, Bruce Montgomery, Peter S. Nelson & Evan Y. Yu

  2. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Michael T. Schweizer, Todd Yezefski, Heather H. Cheng, Elahe Mostaghel, Michael C. Haffner, Brianna Woo, Aaron Lin, Patrick Panlasigui, Nerina McDonald, Michael Lai, Jeannette Hammond, Petros Grivas, Andrew Hsieh, Bruce Montgomery & Evan Y. Yu

  3. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Roman Gulati & Gavin Ha

  4. VA Puget Sound Health Care System, Seattle, WA, USA

    Elahe Mostaghel & Bruce Montgomery

  5. Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Michael C. Haffner, Radhika A. Patel, Navonil De Sarkar, Gavin Ha, Ruth Dumpit, Andrew Hsieh & Peter S. Nelson

  6. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

    Michael C. Haffner

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Contributions

Conceptualization: MTS, RG, PSN, EYY. Collection and assembly of data: MTS, TY, HHC, EM, RD, BW, AL, PP, NM, M, KN, JH, PG, AH, BM, PSN, EYY. Data analysis and interpretation: MTS, RG, EM, MCH, RP, NDS, GH, PSN, EYY. Paper writing-original draft: MTS, RG. Paper review and editing: All authors.

Corresponding author

Correspondence to Michael T. Schweizer.

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Competing interests

MTS: Paid consultant and/or received Honoria from Sanofi, AstraZeneca, PharmaIn and Resverlogix. He has received research funding to his institution from Zenith Epigenetics, Bristol Myers Squibb, Merck, Immunomedics, Janssen, AstraZeneca, Pfizer, Madison Vaccines, Hoffman-La Roche, Tmunity, SignalOne Bio and Ambrx, Inc. HHC: Paid consultant for AstraZeneca. She received royalties from UpToDate. Research funds to her institution were from Clovis Oncology, Color Genomics, Janssen, Medivation, Promontory Therapeutics (formerly Phosplatin) and Sanofi. PSN: Paid consultant for Janssen and Pfizer. He received royalties from UpToDate, Research funds to his institution were from Janssen.

Ethics approval and consent

This clinical study was approved by the Fred Hutchinson Cancer Center institutional review board. All research subjects provided informed consent prior to participating in this study.

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Schweizer, M.T., Gulati, R., Yezefski, T. et al. Bipolar androgen therapy plus olaparib in men with metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 26, 194–200 (2023). https://doi.org/10.1038/s41391-022-00636-0

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