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Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study.

ABSTRACT: PURPOSE:Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS:Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ? 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. RESULTS:One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. CONCLUSION:The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

SUBMITTER: Smith MR

PROVIDER: S-EPMC4383838 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study.

Smith Matthew R MR Sweeney Christopher J CJ Corn Paul G PG Rathkopf Dana E DE Smith David C DC Hussain Maha M George Daniel J DJ Higano Celestia S CS Harzstark Andrea L AL Sartor A Oliver AO Vogelzang Nicholas J NJ Gordon Michael S MS de Bono Johann S JS Haas Naomi B NB Logothetis Christopher J CJ Elfiky Aymen A Scheffold Christian C Laird A Douglas AD Schimmoller Frauke F Basch Ethan M EM Scher Howard I HI

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20140915 30

<h4>Purpose</h4>Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC).<h4>Patients and methods</h4>Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other effica ...[more]

PMID: 25225437

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Project description:Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting.We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (??50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models.One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P?=?0.089). Median TTPP was 7.2 months (95% CI?=?4.5?-?17.2) in the D-naïve group versus 2.6 mo (95% CI?=?1.9?-?3.5) in the D-pretreated group (P?<?0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI?=?2.5?-?4.8) for D-pretreated men (P?<?0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR?=?2.32; 95% CI?=?1.19?-?4.50; P?=?0.013) and marginally significant for PFS (HR?=?1.90; 95% CI?=?0.94?-?3.84; P?=?0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n?=?34), results suggested a trend towards shorter duration of response in D-pretreated patients.The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross-resistance between these two agents.

Project description:Docetaxel chemotherapy remains a standard of care for metastatic castration-resistant prostate cancer (CRPC). Docetaxel modestly increases survival, yet results in frequent occurrence of side effects and resistant disease. An alternate chemotherapy with greater efficacy and minimal side effects is needed. Acquisition of metabolic aberrations promoting increased survival and metastasis in CRPC cells includes constitutive activation of Akt, loss of adenosine monophosphate-activated protein kinase (AMPK) activity due to Ser-485/491 phosphorylation, and overexpression of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoAR). We report that combination of simvastatin and metformin, within pharmacologic dose range (500 nmol/L to 4 ?mol/L simvastatin and 250 ?mol/L to 2 mmol/L metformin), significantly and synergistically reduces C4-2B3/B4 CRPC cell viability and metastatic properties, with minimal adverse effects on normal prostate epithelial cells. Combination of simvastatin and metformin decreased Akt Ser-473 and Thr-308 phosphorylation and AMPK? Ser-485/491 phosphorylation; increased Thr-172 phosphorylation and AMPK? activity, as assessed by increased Ser-79 and Ser-872 phosphorylation of acetyl-CoA carboxylase and HMG-CoAR, respectively; decreased HMG-CoAR activity; and reduced total cellular cholesterol and its synthesis in both cell lines. Studies of C4-2B4 orthotopic NCr-nu/nu mice further demonstrated that combination of simvastatin and metformin (3.5-7.0 ?g/g body weight simvastatin and 175-350 ?g/g body weight metformin) daily by oral gavage over a 9-week period significantly inhibited primary ventral prostate tumor formation, cachexia, bone metastasis, and biochemical failure more effectively than 24 ?g/g body weight docetaxel intraperitoneally injected every 3 weeks, 7.0 ?g/g/day simvastatin, or 350 ?g/g/day metformin treatment alone, with significantly less toxicity and mortality than docetaxel, establishing combination of simvastatin and metformin as a promising chemotherapeutic alternative for metastatic CRPC.

Dataset Information

Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study.

Publications

Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study.

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