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Phase 2 trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer

Abstract

Purpose

Monoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer.

Materials and methods

An open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by PSA ≥ 0.4 ng/ml (post prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline.

Results

Characteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥30% and ≥50% were observed in 25% (n = 5/20) and 10% (n = 2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥30% and ≥50% of 24% (n = 4/17) and 6% (n = 1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2 = 35%), hypertension (grade ≥ 2 = 30%), and edema (grade 1 = 25%, grade 2 = 10%). There was one episode of grade 4 hypertension (cycle 4) and two episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment.

Conclusions

Phenelzine demonstrated efficacy in patients with biochemical recurrent castrate-sensitive prostate cancer. Most treatment-related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer.

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Fig. 1: Changes in PSA relative to phenelzine treatment.
Fig. 2: Longitudinal analysis of PSA levels over time in responding subjects.
Fig. 3: Changes in patient self-report of mood symptoms on treatment.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon request.

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Acknowledgements

Presented in part at the Prostate Cancer Foundation Annual Scientific Retreat October 2016. We thank Mayada Aljehani for statistical analysis and the nurses and research staff at the Ellison Institute for Transformative Medicine of USC, LAC + USC Medical Center and the USC Norris Comprehensive Cancer Center who contributed to this trial.

Funding

USC-Taiwan Center for Translational Research supported by Tsai Family Fund to Jean C. Shih. This work was partially supported by National Cancer Institute Cancer Center Shared Grant award P30CA014089. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. None of the funding sources influenced the design, analysis, or conclusions of the study.

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Authors

Contributions

MEG and JCS were responsible for trial conception and design. MEG, DBA, TD, JP, and DQ were involved in study conduct including patient enrollment, treatment, and data collection. MEG, OC, and PG assembled the data. MEG analyzed the data and drafted the report. All authors critically reviewed the manuscript and approved the final manuscript.

Corresponding authors

Correspondence to Mitchell E. Gross or Jean C. Shih.

Ethics declarations

Ethics approval and consent to participate

The clinical research protocol was approved by the Institutional Review Board (IRB) at the University of Southern California (USC), Los Angeles, California. All patients gave prospective consent to participate in all study procedures.

Conflict of interest

MEG serves as a consultant for Amgen and BeiGene and receives institutional research funding from Clovis Oncology, Glaxo-Smith-Kline, and BeiGene. TBD serves as a consultant for Bayer, Noxopharm, Roche, and Seattle Genetics, is a speaker for Exelixis, and receives institutional research funding from Bayer. DIQ serves as a consultant for Astellas, AstraZeneca, Bayer, Genzyme-Sanofi, Jannsen, Clovis and Pfizer. JCS has a patent entitled Monoamine oxidase inhibitors and methods for treatment and diagnosis of prostate cancer. US Patent No. 9.771,625. The other authors declare no conflicts of interest.

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Gross, M.E., Agus, D.B., Dorff, T.B. et al. Phase 2 trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer. Prostate Cancer Prostatic Dis 24, 61–68 (2021). https://doi.org/10.1038/s41391-020-0211-9

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