Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients

5143 Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been shown to have parodoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of MMPs, growth promotion, inhibition of apoptosis, and regulation of angiogenesis. Increased TIMP-1 has been associated with an unfavorable prognosis in many cancers including breast, colorectal, gastric, head and neck, lung cancer, and lymphomas. Methods: EDTA plasma TIMP-1 was determined from 60 hormone-refractory prostate cancer (HRCaP) patients using the TIMP-1 ELISA from Oncogene Science / Bayer HealthCare, Cambridge, MA. Patients were identified from an institutional database and had metastatic, HRCaP at the time of blood collection, which ranged from <1 month to 14 yrs. after the start of androgen-deprivation therapy (ADT); some patients had also received several chemotherapy regimens by the time of blood collection. Median follow-up was 17 mo. after blood collection and 27/60 patients had died. Overall survival was analyzed using Kaplan-Meier method and Cox modeling on tertiles of the TIMP-1 distribution. Results: The median EDTA plasma TIMP-1 level from the 60 HRCaP patients was 335 ng/ml (range 21 - 1391 ng/ml). Median survival since time of blood collection was 14 mo. Survival differed across TIMP-1 levels (P<0.01, logrank test), in particular the upper tertile of plasma TIMP-1 had a significantly reduced overall survival from the time of blood collection compared to the lowest tertile: A larger confirmatory study which will include a multivariate analysis of known prognostic factors is planned. Conclusions: Elevated plasma TIMP-1 tertile level predicted reduced survival in HRCaP patients. Soluble TIMP-1 deserves further study to determine its predictive and prognostic biomarker potential in a larger cohort of prostate cancer patients. [Table: see text] [Table: see text]

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MER-101–03, a multicenter, phase II study to compare MER-101 20mg tablets to intravenous zoledronic acid 4mg in prostate cancer patients

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.5161 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 5161-5161

Author(s):

C. McHugh ◽

K. Madigan ◽

A. Walsh ◽

J. Fox ◽

T. W. Leonard ◽

...

Keyword(s):

Prostate Cancer ◽

Zoledronic Acid ◽

Bone Metastases ◽

Cancer Patients ◽

Phase Ii ◽

Performance Status ◽

Hormone Refractory Prostate Cancer ◽

Open Label ◽

Secondary Endpoints ◽

Hormone Refractory

5161 Background: The primary objective of this study is to examine the pharmacodynamic effects of two different regimens of zoledronic acid, Orazol 20 mg tablets versus Zometa 4mg IV infusion once-monthly therapy on biomarkers in male bisphosphonate-naïve hormone-refractory prostate cancer patients. Methods: The study is an open-label, multi-center phase II clinical trial to compare oral Orazol 20 mg tablets weekly, to infusions of intravenous Zometa 4mg monthly, in males with hormone-refractory prostate cancer, bone metastases, and no prior bisphosphonate treatment. Patients were assigned into one of three cohorts. The three treatments administered were IV Zometa, 4 mg, 15 minute infusion, Day 0 and Day 28; Orazol po, 20 mg, Days 0, 7, 14, 21, 28, 35, 42, and 49; and Orazol po, 20 mg, Days 0, 1, 2, 3, 28, 35, 42, and 49. The study population consisted of men with hormone refractory prostate cancer as evidenced by history of rising PSA levels (last 2 of 3 PSA levels must be above nadir), who are bisphosphonate-naive, and have radiographically-confirmed bone metastases. Efficacy assessments: The primary endpoints are the assessment of response of four biomarkers, urinary NTX, serum CTX, serum bone specific alkaline phosphatase, and serum calcium on days -7, 0, 7, 14, 21, 28, 35, 42, 49, and 56. Secondary endpoints are assessments of performance and pain scores based on ECOG performance status, BPI, and analgesic use. Safety assessments include physical examinations, vital signs and body weight, hematology panel, urinalysis, and blood chemistry panel. Results: The results demonstrated a rapid decrease for all four biomarkers. This decrease was seen at seven days, and was sustained throughout the study. There were no statistically significant differences between any of the treatments in the primary and secondary endpoints. Conclusions: From the results of MER-101–03, Orazol weekly therapy appears to be as effective as Zometa, based on the biomarkers analyzed. Orazol offers a substantial improvement in therapy over IV infusion for patients, with efficacy that is at least comparable based on the results obtained here. No significant financial relationships to disclose.

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