Previous data suggests that co-targeting mammalian target of rapamycin and angiogenic pathways may potentiate effects of cytotoxic chemotherapy. We studied combining mammalian target of rapamycin and vascular endothelial growth factor inhibition with docetaxel in castrate-resistant prostate cancer (CRPC).Methods
Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Docetaxel and bevacizumab were given intravenously day 1 with everolimus orally daily on a 21-day cycle across 3 dose levels (75:15:2.5, 75:15:5, and 65:15:5; docetaxel mg/m2, mg/kg bevacizumab, and mg everolimus, respectively). Maintenance therapy with bevacizumab/everolimus without docetaxel was allowed after ≥ 6 cycles.Results
Forty-three subjects were treated across all dose levels. Maximal tolerated doses for the combined therapies observed in the phase 1B portion of the trial were: docetaxel 75 mg/m2, bevacizumab 15 mg/kg, and everolimus 2.5 mg. Maximal prostate-specific antigen decline ≥ 30% and ≥ 50% was achieved in 33 (79%) and 31 (74%) of patients, respectively. Best response by modified Response Evaluation Criteria In Solid Tumors criteria in 25 subjects with measurable disease at baseline included complete or partial response in 20 (80%) patients. The median progression-free and overall survival were 8.9 months (95% confidence interval, 7.4-10.6 months) and 21.9 months (95% confidence interval, 18.4-30.3 months), respectively. Hematologic toxicities were the most common treatment-related grade ≥ 3 adverse events including: febrile neutropenia (12; 28%), lymphopenia (12; 28%), leukocytes (10; 23%), neutrophils (9; 21%), and hemoglobin (2; 5%). Nonhematologic grade ≥ 3 adverse events included: hypertension (8; 19%), fatigue (3; 7%), pneumonia (3; 7%), and mucositis (4; 5%). There was 1 treatment-related death owing to neutropenic fever and pneumonia in a patient treated at dose level 3 despite dose modifications and prophylactic growth factor support.Conclusions
Docetaxel, bevacizumab, and everolimus can be safely administered in CRPC and demonstrate a significant level of anticancer activity, meeting the predetermined response criteria. However, any potential benefit of combined therapy must be balanced against increased risk for toxicities. Our results do not support the hypothesis that this combination of agents improves upon the results obtained with docetaxel monotherapy in an unselected population of chemotherapy-naive patients with CRPC.Micro-Abstract
We conducted a study of combined treatment with docetaxel, bevacizumab, and everolimus in patients with chemotherapy-naive metastatic castrate-resistant prostate cancer. Although we establish a safe dose for coadministration of these 3 agents and our early results suggested encouraging levels of anti-cancer efficacy, our final results do not support further exploration of this treatment regimen for castrate-resistant prostate cancer.