Assessing cardiac risk using heart rate variability in a phase II study of androgen-deprivation therapy and bevacizumab in noncastrate metastatic prostate cancer patients.

Abstract

TPS244 Background: Androgen-deprivation therapy (ADT) is standard treatment in noncastrate patients with metastatic or recurrent prostate cancer (PC) with a median duration of response of 12-18 months. Preclinical data shows castration is correlated to decreased vascular endothelial growth factor (VEGF) expression and a synergistic effect with ADT and VEGF inhibition on tumor growth. This may lead to increased PC cell death and prolonged therapeutic effects of medical castration. Safety and biological effects of combination therapy need to be established. SEER database and other studies show PC patients treated with ADT were at increased risk of diabetes, myocardial infarction (MI) and sudden cardiac arrest. Cardiovascular events are more prevalent in anti-VEGF antibody (bevacizumab; BEV) treated patients. This study will assess autonomic dysregulation as a predictor for cardiovascular outcomes, which can be achieved via heart rate variability (HRV) monitoring where depressed HRV is associated with poor cardiac outcomes after MI and in the general population. HRV monitoring is a novel approach in cancer patients. Methods: Patients with prostatic adenocarcinoma, rising PSA after primary local therapy or surgery, and a PSA doubling time of < 6 months or evidence of metastatic disease are eligible. All patients must have adequate cardiac function and a Karnofsky PS ≥ 70%. Exclusions include MI, thromboembolic, or major hemorrhagic event within 6 months. 60 patients are planned for enrollment. Patients receive BEV 15 mg/kg every 3 weeks and ADT (leuprolide or goserelin) every 3 months for 3 cycles (1 cycle = 12 weeks; total 36 weeks). Patients receive bicalutamide 50 mg PO daily for the first 4 weeks. Cardiovascular status is assessed by serial cardiac biomarkers, echocardiogram (week 0 and 37) and 24-hour Holter monitor testing (week 0, 15, and 37) for HRV. The primary endpoint is cardiovascular outcome and adverse events. The secondary endpoint is PSA kinetics and duration of PSA response. Correlative studies to assess cytokine, circulating endothelial cell, and cell signaling protein levels are planned. Six patients have been enrolled to date. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech