Introduction:

High prostate eicosapentaenoic fatty acid (EPA) levels have been associated with a significant reduction of prostate cancer upgrading to grade group (GG) ≥2 in men with GG1 prostate cancer on active surveillance. The current phase IIb randomized pre-prostatectomy placebo-controlled trial assessed the effect of a monoacylglyceride-EPA (MAG-EPA) supplement on prostate cancer aggressiveness in 130 men diagnosed with prostate cancer. 

Methods:

Men diagnosed with GG ≥2 prostate cancer and undergoing radical prostatectomy between 2015-2017 were randomized to either 3g/day of MAG-EPA (n=65) or placebo (n=65) for seven weeks prior to radical prostatectomy and for up to one year after surgery (NCT02333435). The primary outcome was the cancer proliferation index quantified by automated image analysis of tumor nuclear Ki-67 expression using standardized prostatectomy tissue microarrays. One exploratory clinical outcome was grade reclassification from baseline biopsy at prostatectomy. Stool samples were collected in a sub-group of consent patients (n=42) for gut microbiome and fecal short-chain fatty acid analyses, using 16srRNA sequencing and targeted metabolomics, respectively.

Results:

Men randomized to MAG-EPA had four-fold higher EPA levels in prostate tissues compared to those on placebo. The primary outcome was the cancer proliferation index measured by Ki-67 expression which was not statistically different between intervention (3.10%) and placebo (2.85%) groups. In the per protocol analyses, the adjusted estimated effect of MAG-EPA was greater but remained non-significant. However, there was a significant increase in size and proliferative index of tumor lymphoid aggregates in MAG-EPA treated prostate cancer, suggesting an immune mediated effect. In exploratory analyses, the MAG-EPA group had more cancer pathological downgrade and less cancer upgrade at prostatectomy, compared to the placebo group (p=0.024). Gut microbiota analysis revealed that the cancer up-grading reduction in pre-prostatectomy prostate cancer patients taking MAG-EPA was associated with a reduction of gut Ruminococaceae and fecal butyrate levels.

Conclusion:

Our results suggest that lowering gut butyrate, a known immune modulator, may partly explain the beneficial effect of MAG-EPA on prostate cancer aggressiveness. More studies are needed to better understand the biological and clinical outcomes following this concentrated EPA supplementation and determine if and how it can benefit prostate cancer patients.

Funding: This work was mainly supported by the Canadian Cancer Society (Grant #702569), and Prostate Cancer Canada (#400345)..