Phase II Trial Results Show Promise for Phenelzine in Prostate Cancer

Phase II trial results published in Prostate Cancer and Prostatic Diseases found that phenelzine (Nardil), a monoamine oxidase (MAO) inhibitor typically used as an antidepressant, showed promise for patients with biochemical recurrent castrate-sensitive prostate cancer.¹

As seen in previously conducted pre-clinical models, MAO inhibitors in prostate cancer were found to disrupt androgen receptor signaling, decreasing the growth and spread of prostate cancer. Moreover, unlike hormone therapy which comes with serious side effects, MAO inhibitors are able to avoid these side effects through dietary changes and careful avoidance of drug interactions. 

“The most exciting implication of this work is that it may open up an entirely new pathway which can be applied to prostate cancer treatment,” first author Mitchell E. Gross, MD, PhD, a medical oncologist and research director at the Lawrence J. Ellison Institute for Transformative Medicine of USC, said in a press release.² “Specifically, the [monoamine oxidase A; MAOA] enzyme has been identified as important to prostate cancer in a variety of laboratory and clinical studies, but ours is the first published study suggesting any benefit of actually treating patients with MAOA inhibitors.” 

The study enrolled 20 patients with biochemical recurrent prostate cancer defined by prostate specific antigen (PSA) ≥ 0.4 ng/ml (post prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy), with no metastasis on imaging, and normal androgen levels. Participants were given 30 mg of phenelzine orally twice daily, and their mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint for the study was the proportion of patients who achieved a PSA decline of ≥50% from baseline.

Maximal PSA declines ≥30% and ≥50% were observed in 25% (n = 5/20) and 10% (n = 2/20) of the subjects, respectively. At 12 weeks, 17 of the participants remained on treatment with PSA declines ≥30% and ≥50% of 24% (n = 4/17) and 6% (n = 1/17), respectively. Moreover, the HADS questionnaire answers displayed a significant decrease in anxiety with no changes seen in depressive symptoms on treatment. 

Common toxicities observed included dizziness (grade 1 = 45%, grade 2 = 35%), hypertension (grade ≥ 2 = 30%), and edema (grade 1 = 25%, grade 2 = 10%). One episode of grade 4 hypertension (cycle 4) and 2 episodes of grade 3 syncope (cycle 12 and cycle 14) required patients to discontinue treatment. 

“It is important to note that all of the patients were asymptomatic from a prostate cancer standpoint on this trial,” said Gross. 

Notably, this study lacked a placebo comparison group and only studied a small cohort. The researchers indicated that further research is necessary to determine if MAO inhibitors, used alone or in combination with other agents, could delay clinical progression and metastasis. 

Additional studies have been planned though, and senior author Jean Shih, PhD, a professor in USC’s School of Pharmacy, has already patented a second-generation MAO inhibitor tagged with a substance that may help doctors see where the cancer has spread.²

“Our next steps are to try to identify patients that are most likely to benefit from MAO treatment with blood and other testing strategies,” Gross said. “Also, we want to explore how MAO inhibitors can be safely given along with other agents in a way which maximizes clinical benefits while also minimizing risks of adverse reactions.” 

References:

1. Gross ME, Agus DB, Dorff TB, et al. Phase 2 trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer. Prostate Cancer and Prostatic Diseases; 2020. doi:10.1038/s41391-020-0211-9. 

2. Repurposed antidepressant could be a new treatment for recurrent prostate cancer [news release]. Published March 3, 2020. news.usc.edu/166277/antidepressant-prostate-cancer-mao-inhibitor-phenelzine/. Accessed March 3, 2020.