Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study.

BACKGROUND: We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT). Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in. METHODS: Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT. BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL). RESULTS: Twenty-nine of 33 patients received BAT following the ADT lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys. CONCLUSIONS: BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT. Prostate 76:1218-1226, 2016. © 2016 Wiley Periodicals, Inc.

[Energy expenditure on different physical activities of rural adults in North China].

UNLABELLED: To test the energy metabolism of healthy adults in rural north China and to obtain the data of energy expenditure on different physical activities, in order to provide the basis for the Dietary Reference Intakes for Chinese people and the prevention and treatment of diseases related to energy and nutrition imbalance. METHOD: The energy expenditures on different physical activities of 30 healthy adult men and women were investigated under strictly controlled experimental conditions by using portable cardiopulmonary function determinator k4b2 to examine the oxygen consumption (VO2) and carbon dioxide production (VCO2) during basal metabolic conditions and seven kinds of physical activities (walking, brisk walking, jogging, cycling, stair climbing, and watching TV). The content of 24-hour urine nitrogen was measured by micro Kjeldahl method. Combining with the change of body weight, the energy expenditures on different physical activities of normal adult men and women in north China were obtained. RESULTS: The average energy expenditure on physical activities (kJ x h(-1) x kg(-1)) were: walking 12.60 +/- 5.54 (11.46 +/- 2.19 for male and 15.47 +/- 6.97 for female), brisk walking 20.79 +/- 10.46 (15.95 +/- 3.59 for male and 25.33 +/- 12.70 for female), jogging 34.78 +/- 16.00 (30.45 +/- 5.07 for male and 38.84 +/- 21.58 for female) cycling 16.47 +/- 3.95 (14.77 +/- 2.57 for male and 18.74 +/- 4.85 for female), going up stairs 23.55 +/- 5.05 (23.61 +/- 3.43 for male and 23.49 +/- 6.41 for female) going down stairs 12.46 +/- 6.30 (10.43 +/- 1.27 for male and 14.49 +/- 8.48 for female) and watching TV 3.85 +/- 1.97 (3.56 +/- 0.86 for male and 4.16 +/- 2.79 for female). CONCLUSION: The average energy expenditure on physical activities of males was lower than that of females (P < 0.05), except of going up stairs, which was roughly equal in males and females. The average energy expenditure on various physical activities was different. Walking, watching TV and going downstairs are low-intensity physical activities; brisk walking, cycling and climbing upstairs are medium-intensity physical activities; and jogging is a high-intensity physical activity.

T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer.

PURPOSE: Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. PATIENTS AND METHODS: We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. RESULTS: Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T-cell infiltration and PD-L1 expression as compared with a cohort of untreated, matched controls. However, the CD8+ T-cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment, as well as an increase in PD-L1, there was no difference in the CD8+ T-cell infiltrate as compared with degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with degarelix alone. CONCLUSIONS: Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.

Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study.

Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs). Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment. However, preclinical models suggest that AR overexpression represents a therapeutic liability that can be exploited via exposure to supraphysiologic testosterone to promote CRPC cell death. Preclinical data supported a pilot study in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28). After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone therapy monotherapy. Castrating therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, a strategy termed bipolar androgen therapy (BAT). BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients). Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving androgen-ablative therapies after BAT, suggesting that BAT may also restore sensitivity to ADTs. BAT shows promise as treatment for CRPC and should be further evaluated in larger trials.