TT-701

Selective androgen receptor modulators (SARMs), because of their preferential muscle vs prostate selectivity, are being developed for muscle-wasting conditions. Oral SARMs suppress high-density lipoprotein cholesterol (HDL-C) but their effects on functional capacity and atherogenic potential of HDL particles are unknown.

To determine the effects of an oral SARM (OPK-88004) on cholesterol efflux capacity, HDL particle number and size, apolipoprotein particle number and size and HDL subspecies

We measured cholesterol efflux capacity (CEC); HDL particle number and size; APOB; APOA1; and protein-defined HDL subspecies associated with coronary heart disease (CHD) risk in men, who had undergone prostatectomy for low-grade prostate cancer during 12-week treatment with placebo or 1, 5, or 15 mg of an oral SARM (OPK-88004).

SARM significantly suppressed HDL-C (P < .001) but HDL particle size did not change significantly. SARM had minimal effect on CEC of HDL particles (change + 0.016, –0.036, +0.070, and –0.048%/µmol-HDL/L–1 at 0, 1, 5, and 15 mg SARM, P = .045). SARM treatment suppressed APOAI (P < .001) but not APOB (P = .077), and reduced APOA1 in HDL subspecies associated with increased (subspecies containing α2-macroglobulin, complement C3, or plasminogen) as well as decreased (subspecies containing APOC1 or APOE) CHD risk; relative proportions of APOA1 in these HDL subspecies did not change. SARM increased hepatic triacylglycerol lipase (HTGL) (P < .001).

SARM treatment suppressed HDL-C but had minimal effect on its size or cholesterol efflux function. SARM reduced APOA1 in HDL subspecies associated with increased as well as decreased CHD risk. SARM-induced increase in HTGL could contribute to HDL-C suppression. These data do not support the simplistic notion that SARM-associated suppression of HDL-C is necessarily proatherogenic; randomized trials are needed to determine SARM’s effects on cardiovascular events.

Androgen deficiency is common among prostate cancer survivors, but many guidelines consider history of prostate cancer a contraindication for testosterone replacement. We determined the safety and efficacy of a selective androgen receptor modulator (OPK-88004) in symptomatic, testosterone-deficient men who had undergone radical prostatectomy for low-grade, organ-confined prostate cancer.

In this placebo-controlled, randomized, double-blind trial, 114 men, ≥19 years of age, who had undergone radical prostatectomy for low-grade, organ-localized prostate cancer, undetectable PSA (<0.1 ng/mL) for ≥2 years after radical prostatectomy and testosterone deficiency were randomized in stages to placebo or 1, 5, or 15 mg OPK-88004 daily for 12 weeks. Outcomes included PSA recurrence, sexual activity, sexual desire, erectile function, body composition, muscle strength and physical function measures, mood, fatigue, and bone markers.

Participants were on average 67.5 years of age and had severe sexual dysfunction (mean erectile function and sexual desire domain scores 7.3 and 14.6, respectively). No participant experienced PSA recurrence or erythrocytosis. OPK-88004 was associated with a dose-related increase in whole-body (P < 0.001) and appendicular (P < 0.001) lean mass and a significantly greater decrease in percent body fat (P < 0.001) and serum alkaline phosphatase (P < 0.001) than placebo. Changes in sexual activity, sexual desire, erectile function, mood, fatigue, physical performance, and bone markers did not differ among groups (P = 0.73).

Administration of OPK-88004 was safe and not associated with PSA recurrence in androgen-deficient men who had undergone radical prostatectomy for organ-confined prostate cancer. OPK-88004 increased lean body mass and decreased fat mass but did not improve sexual symptoms or physical performance.