ABSTRACT
BACKGROUND: Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity. METHODS: Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1-12) and 2 in arm B (range 1-9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p = 0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9-6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm. CONCLUSIONS: Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC. ClinicalTrials.gov number: NCT01260688.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged , Aged, 80 and over , Alkaline Phosphatase/blood , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bone and Bones/enzymology , Collagen Type I/blood , DNA, Neoplasm/genetics , Dasatinib , Docetaxel , Drug Resistance, Neoplasm , Humans , Male , Middle Aged , Mutation , Peptides/blood , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/genetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/pharmacology , Quinazolines/administration & dosage , Quinazolines/adverse effects , Quinazolines/pharmacology , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sequence Analysis, DNA , Taxoids , Thiazoles/administration & dosage , Thiazoles/adverse effects , Thiazoles/pharmacology , Treatment Outcome , src-Family Kinases/antagonists & inhibitorsABSTRACT
Ductal carcinoma of the prostate is a rare histologic subtype of prostate carcinoma. It represents 0.4% to 0.8% of all prostate cancers and is associated with a poor prognosis. Given the paucity of cases reported in the literature on ductal prostate carcinoma, little is known about how this cancer responds to cytotoxic chemotherapy. We report the case of a 56-year-old male who presented to our clinic with hemoptysis, cough and hematuria and was found to have metastatic ductal carcinoma of the prostate. He was initiated on docetaxel chemotherapy, which has been previously shown to improve overall survival in patients with metastatic prostate adenocarcinoma, but has never been studied in this less common subtype of prostate cancer. To the best of our knowledge, the following is the first reported case of a patient with metastatic ductal carcinoma of the prostate responding to docetaxel chemotherapy.
