Biomarker Development Trial of Satraplatin in Patients with Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: In the phase III SPARC trial, satraplatin, an oral platinum analogue, demonstrated anticancer activity in men with metastatic castration-resistant prostate cancer (mCRPC). Repeat biopsies are uncommon in mCRPC, limiting the feasibility of tissue-based biomarkers. This phase II study sought to evaluate the feasibility and utility of blood-based biomarkers to identify platinum-sensitive mCRPC. METHODS: Patients with mCRPC who had progressed on docetaxel were enrolled at a single center from 2011 to 2013. Subjects received satraplatin 80 mg/m2 by mouth daily on days 1-5 and prednisone 5 mg PO twice daily, on a 35-day cycle. Serial peripheral blood samples were collected for biomarker assessment. RESULTS: Thirteen docetaxel-refractory mCRPC patients were enrolled, with a median age of 69 years (range 54-77 years) and median PSA of 71.7 ng/mL (range 0.04-3057). Four of 13 patients (31%) responded to satraplatin (defined as a PSA decline of ≥30%). Responders demonstrated improved time to disease progression (206 vs. 35 days, HR 0.26, 95% CI, 0.02-0.24, P = .003). A 6-gene peripheral blood RNA signature and serum tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were assessed as biomarkers, but neither was significantly associated with response to satraplatin. CONCLUSION: In this small series, one-third of mCRPC patients responded to platinum-based chemotherapy. Peripheral blood biomarker measurement is feasible in mCRPC, though the biomarkers we investigated were not associated with platinum response. Other biomarkers, such as DNA damage repair mutations, should be evaluated.

Risk of venous thromboembolism in patients with cancer treated with Cisplatin: a systematic review and meta-analysis.

PURPOSE: Several reports suggest that cisplatin is associated with an increased risk of thromboembolism. However, because the excess risk of venous thromboembolic events (VTEs) with cisplatin-based chemotherapy has not been well described, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of VTEs associated with cisplatin-based chemotherapy. METHODS: PubMed was searched for articles published from January 1, 1990, to December 31, 2010. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based versus non-cisplatin-based chemotherapy in patients with solid tumors. Data on all-grade VTEs were extracted. Study quality was calculated using Jadad scores. Incidence rates, relative risks (RRs), and 95% CIs were calculated using a random effects model. RESULTS: A total of 8,216 patients with various advanced solid tumors from 38 randomized controlled trials were included. The incidence of VTEs was 1.92% (95% CI, 1.07 to 2.76) in patients treated with cisplatin-based chemotherapy and 0.79% (95% CI, 0.45 to 1.13) in patients treated with non-cisplatin-based regimens. Patients receiving cisplatin-based chemotherapy had a significantly increased risk of VTEs (RR, 1.67; 95% CI, 1.25 to 2.23; P = .01). Exploratory subgroup analysis revealed the highest RR of VTEs in patients receiving a weekly equivalent cisplatin dose > 30 mg/m(2) (2.71; 95% CI, 1.17 to 6.30; P = .02) and in trials reported during 2000 to 2010 (1.72; 95% CI, 1.27 to 2.34; P = .01). CONCLUSION: Cisplatin is associated with a significant increase in the risk of VTEs in patients with advanced solid tumors when compared with non-cisplatin-based chemotherapy.

Arterial thromboembolism in cancer patients treated with cisplatin: a systematic review and meta-analysis.

Cisplatin has been associated with an increased risk of arterial thromboembolic events (ATEs). However, because this association is mostly based on case reports and retrospective studies, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of ATEs associated with cisplatin. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based vs non-cisplatin-based chemotherapy in patients with solid tumors, which were identified from PubMed articles published between 1990 and 2010. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 8216 patients from 38 trials were included. Among patients treated with cisplatin-based chemotherapy, the summary incidence of ATEs was 0.67% (95% CI = 0.40% to 0.95%), and the RR of ATEs was 1.36 (95% CI = 0.86 to 2.17; P = .19). No increase in ATEs was detected in any prespecified subgroup.

Impact of the CKD-EPI equation for estimating renal function on eligibility for cisplatin-based chemotherapy in patients with urothelial cancer.

BACKGROUND: Although a creatinine clearance (CrCl) of <60 mL/min, as calculated by the Cockroft-Gault (CG) equation, is a commonly used threshold for "cisplatin-ineligibility," the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has recently emerged as a more accurate method of estimating renal function. We sought to determine the impact of using the CKD-EPI equation for estimating renal function on cisplatin eligibility. METHODS: All patients pathologically diagnosed with muscle invasive and/or metastatic bladder urothelial carcinoma (T2-4, N or M positive) at Mount Sinai Medical Center between January 1, 2000, and January 27, 2011, were identified. For each patient, CrCl was estimated by using the CG equation and glomerular filtration rate (GFR) was estimated by using the CKD-EPI equation. The patients were considered cisplatin-ineligible if CrCl <60 mL/min or if GFR was <60 mL/min per 1.73 m(2). RESULTS: A total of 116 patients were included. The median CrCl estimated by CG was 58.93 mL/min, whereas the median GFR estimated by CKD-EPI was 64.67 mL/min per 1.73 m(2). When using the CG formula, 53% of our cohort was cisplatin ineligible, whereas 46% of the cohort was ineligible when using the CKD-EPI formula. The probability of deeming a patient ineligible when using the CG formula was 17% higher than the probability of deeming a patient ineligible when using the CKD-EPI formula: PR 1.17 (95% CI, 1.03-1.34); P = .0203. CONCLUSION: In our retrospective study, the CKD-EPI formula was less likely to deem a patient ineligible for cisplatin-based therapy compared with the CG formula. This finding was hypothesis generating, and prospective evaluation is necessary to determine the clinical relevance of using this more accurate method of renal function assessment in chemotherapy decision making.

Clinical development of cabazitaxel for the treatment of castration-resistant prostate cancer.

Castration resistant prostate cancer has historically been considered chemotherapy insensitive. However, the approval of estramustine phosphate, mitoxantrone, and docetaxel, over the past few decades, has challenged this notion. Despite these advances, until recently, only docetaxel had been shown to improve survival in patients with castration-resistant disease, and there has been no standard treatment options available for men with disease progression on docetaxel. In the last year, cabazitaxel, a novel taxane with decreased affinity for ATP-dependent drug efflux pump P-glycoprotein, became the first cytotoxic agent to demonstrate an improvement in survival in men with docetaxel-refractory disease, and has received regulatory approval for treatment in this setting. In this review, we examine the clinical development of cabazitaxel for the treatment of castration-resistant prostate cancer, as well as rationale and direction of future therapeutic investigation.

Retrospective analysis of satraplatin in patients with metastatic urothelial cancer refractory to standard platinum-based chemotherapy.

UNLABELLED: Satraplatin is a novel platinum agent with favorable clinical attributes including oral bioavailability and lack of significant treatment-associated neuropathy and nephropathy. Furthermore, preclinical studies have shown that satraplatin is active is cisplatin-resistant tumors. We retrospectively evaluated the activity of satraplatin in patients with cisplatin or carboplatin-refractory urothelial carcinoma and demonstrated lack of significant antitumor activity in this population. BACKGROUND: Satraplatin is an oral platinum analogue with antitumor activity in cisplatin-resistant cells lines. The activity of satraplatin in patients with metastatic cancers of the urothelial tract refractory to standard platinum agents has not previously been reported. METHODS: We previously reported a phase I study of the safety and pharmacokinetics of satraplatin in patients with refractory solid tumors and varying degrees of renal impairment. Given that the majority of patients enrolled in the study had metastatic cancers of the urothelial tract, and all patients were treated with a uniform dose and schedule, we performed a retrospective analysis to describe the activity of satraplatin in this cohort. RESULTS: A total of 12 patients with metastatic cancers of the urothelial tract were enrolled. The majority (83%) had transitional cell carcinomas, whereas 2 patients (17%) had adenocarcinomas. All patients were treated previously with platinum agents; 6 patients (50%) had previously received cisplatin and 8 patients (67%) had previously received carboplatin. Patients were treated with a median of 1.5 cycles of satraplatin (range, 1-4). There were no objective responses; 1/12 (8%) patients experienced transient stable disease and 11/12 (92%) experienced disease progression as best response. CONCLUSIONS: Treatment with satraplatin in patients with metastatic cancers of the urothelial tract who had progressed on standard platinum-based chemotherapy resulted in negligible antitumor activity. These conclusions are limited by the retrospective nature of the analysis and the phase I population from which the data were derived. The activity of satraplatin in patients with metastatic cancers of the urothelial tract who have been less heavily pretreated is unknown.