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Purpose: Three small retrospective studies have suggested that patients undergoing continuous androgen deprivation (CAD) have superior survival and time to progression if lower castrate levels of testosterone (< 0.7 nmol/L) are achieved. Evidence from prospective large studies has been lacking. Patients and Methods: The PR-7 study randomly assigned patients experiencing biochemical failure after radiation therapy or surgery plus radiation therapy to CAD or intermittent androgen deprivation. The relationship between testosterone levels in the first year and cause-specific survival (CSS) and time to androgen-independent progression in men in the CAD arm was evaluated using Cox regression. Results: There was a significant difference in CSS (P = .015) and time to hormone resistance (P = .02) among those who had first-year minimum nadir testosterone ≤ 0.7, > 0.7 to ≤ 1.7, and ≥ 1.7 nmol/L. Patients with first-year nadir testosterone consistently > 0.7 nmol/L had significantly higher risks of dying as a result of disease (0.7 to 1.7 nmol/L: hazard ratio [HR], 2.08; 95% CI, 1.28 to 3.38; > 1.7 nmol/L: HR, 2.93; 95% CI, 0.70 to 12.30) and developing hormone resistance (0.7 to 1.7 nmol/L: HR, 1.62; 95% CI, 1.20 to 2.18; ≥ 1.7 nmol/L: HR, 1.90; 95% CI, 0.77 to 4.70). Maximum testosterone ≥ 1.7 nmol/L predicted for a higher risk of dying as a result of disease (P = .02). Conclusion: Low nadir serum testosterone (ie, < 0.7 mmol/L) within the first year of androgen-deprivation therapy correlates with improved CSS and duration of response to androgen deprivation in men being treated for biochemical failure undergoing CAD.

VT-464 is a novel, nonsteroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. This study evaluates the anticancer activity of VT-464 compared with abiraterone (ABI) in castrate-resistant prostate cancer cell lines and xenograft models that are enzalutamide (ENZ)-responsive (C4-2) or ENZ-resistant (MR49C, MR49F). In vitro, androgen receptor (AR) transactivation was assessed by probasin luciferase reporter, whereas AR and AR-regulated genes and steroidogenic pathway enzymes were assessed by Western blot and/or qRT-PCR. The MR49F xenograft model was used to compare effects of oral VT-464 treatment to vehicle and abiraterone acetate (AA). Steroid concentrations were measured using LC-MS chromatography. VT-464 demonstrated a greater decrease in AR transactivation compared with ABI in C4-2 and both ENZ-resistant cell lines. At the gene and protein level, VT-464 suppressed the AR axis to a greater extent compared with ABI. Gene transcripts StAR, CYP17A1, HSD17B3, and SRD5A1 increased following treatment with ABI and to a greater extent with VT-464. In vivo, intratumoral androgen levels were significantly lower after VT-464 or AA treatment compared with vehicle, with the greatest decrease seen with VT-464. Similarly, tumor growth inhibition and PSA decrease trends were greater with VT-464 than with AA. Finally, an AR-antagonist effect of VT-464 independent of CYP17A1 inhibition was observed using luciferase reporter assays, and a direct interaction was confirmed using an AR ligand binding domain biolayer interferometry. These preclinical results suggest greater suppression of the AR axis with VT-464 than ABI that is likely due to both superior selective suppression of androgen synthesis and AR antagonism. Mol Cancer Ther; 14(1); 59–69. ©2014 AACR.

The management of small, incidental testicular masses found on scrotal ultrasound is controversial. Although these neoplasms are classically treated with surgical excision, ultrasound surveillance has been proposed as an alternative to surgery. We reviewed our experience of ultrasound surveillance for small testicular masses at Mount Sinai Hospital Fertility Clinic from 2001 to 2008, offered to all patients with subcentimeter, incidentally discovered hypoechoic testicular lesions. Patient age, semen parameters, the size and growth of the lesion on serial ultrasounds, need for surgery and pathological diagnosis were collected in a database. Of 4,418 patients evaluated 46 (1%) met the study inclusion criteria. Mean age was 35 years, and 39 patients (85%) presented with infertility. Semen analysis revealed azoospermia, oligospermia and normospermia in 15, 18 and 7 patients, respectively, and was unavailable in 6. Mean ultrasound followup was 253 days and mean number of ultrasounds was 2.8. Mean lesion diameter was 4.3 mm (range 1 to 10). There were 38 patients with serial ultrasound followup only with a mean growth of 0.5 mm per year (95% CI -2.2-3.3). Three patients underwent immediate surgery and 5 underwent surgery following a period of ultrasound followup. Indications for surgery were interval growth in 2 patients and patient choice in 6. Larger size (p = 0.02) and presence of vascular flow (p <0.01) were associated with intervention. One patient underwent radical orchiectomy for pure seminoma identified due to interval growth from 3 to 6 mm at 3 months. The other 7 masses excised with partial orchiectomy were benign. Ultrasound surveillance of small (less than 1 cm) incidental testicular masses is a safe alternative to immediate surgical removal.