Matthew D. Galsky

Background: Once castration resistance is documented and secondary hormone therapy is ineffective, standard treatment of metastatic prostate cancer is docetaxel, with bisphosphonates and radiopharmaceuticals administered to treat bone symptoms. To improve outcomes, numerous studies have evaluated docetaxel in combination with other agents. Here, results for docetaxel-based combination therapy in castration-resistant prostate cancer (CRPC) are reviewed. Materials and methods: Relevant studies were identified in databases of published literature, clinical trials, and conference abstracts using the search terms docetaxel and prostate, with additional searches carried out for identified agents. Results: Numerous classes of agents have been combined with docetaxel in phase II studies in CRPC, including tyrosine kinase inhibitors, antiangiogenic agents, bone-targeted agents, BCL-2 inhibitors, chemotherapies, immunologic agents, and vitamin D analogs. In several cases, promising rates of prostate-specific antigen response, tumor response, and survival have been reported. However, some combinations have caused increased toxicity. Phase III trials with docetaxel plus GVAX or DN-101 were terminated because of lower survival; phase III trials with docetaxel plus bevacizumab, aflibercept, dasatinib, zibotentan, atrasentan, or lenalidomide are ongoing. Conclusions: Docetaxel-based doublet therapy remains an active investigational strategy in CRPC. Further phase III data are awaited to determine whether survival can be extended compared with docetaxel alone.

Preclinical and clinical data support the importance of signaling via the androgen receptor even in the setting of castration-resistant prostate cancer. However, the role of additional hormonal manipulations in patients progressing on cytotoxic chemotherapy has not been well defined. Recently, the novel lyase inhibitor, abiraterone acetate, has shown activity in patients with docetaxel-refractory disease [1, 2]. The activity of ketoconazole in this clinical state has not previously been described. We carried out an institutional review board-approved retrospective review to evaluate the activity of ketoconazole in patients with castration-resistant metastatic prostate cancer who had progressed while on prior treatment with docetaxel. Patients treated from 1 January 2005 to 6 June 2008 were identified through record reviews. Eleven patients (median age = 73 years) were identified with characteristics detailed in Table 1. None of the patients had received ketoconazole before docetaxel. The median number of cytotoxic regimens administered before ketoconazole was 1 (range 1–3). With ketoconazole treatment, 4 of 11 (36%; 95% confidence interval 8% to 65%) patients achieved a ≥50% post-treatment decline in prostate-specific antigen (PSA) including three of four patients who did not achieve a ≥50% PSA decline with prior docetaxel and three of four patients treated with ketoconazole without steroids. Reasons for discontinuation of ketoconazole included progression in five patients and toxicity in one patient; five patients remain on treatment. Based on this small retrospective analysis, the inhibitor of adrenal androgen synthesis, ketoconazole, retains activity in patients with docetaxel-refractory prostate cancer. This readily accessible agent could be considered for treatment of patients in this disease state lacking clinical trial options, if not utilized before the initiation of docetaxel.

Purpose: To describe a phase II study design to evaluate the activity of novel anti-cancer agents that focuses on molecular pathogenesis rather than tumor histology. Methods: We propose an enrichment design that enrolls patients across histologies expressing target X and incorporates randomized discontinuation of drug Y after an initial treatment period to evaluate for potential cystostatic activity. Results: We are currently evaluating the activity of lapatinib in patients with HER-2 amplified solid tumors using the target-specific, histology-independent, randomized discontinuation design. Patients receive treatment with lapatinib for an initial 12-week period. After restaging, patients with disease progression are removed from study, patients achieving an objective response continue treatment, and patients with stable disease are randomized to continue lapatinib versus initiate treatment with placebo. The primary endpoints are to evaluate the objective response rate during the initial treatment period and to evaluate the proportion of patients progression-free 12 weeks post-randomization. Conclusion: The target-specific, histology-independent, randomized discontinuation design is an attractive alternative to the traditional phase II design for the development of “targeted” therapeutics.

Breakthroughs in understanding the pathogenesis of renal cell carcinoma have led to recent therapeutic advances in this disease. However, the US FDA approval of sunitinib and sorafenib (and soon temsirolimus) after successful Phase III trials must also be attributed to the work of clinical investigators over the past decade defining the outcomes and major prognostic factors in patients with advanced renal cell carcinoma. Those past studies have been critical in providing a context for the interpretation of future trials with novel agents, optimizing patient selection for specific therapeutic approaches and identifying appropriate variables for patient stratification on randomized trials. This review will focus on studies that define the outcome and prognosis in advanced renal cell carcinoma.

BACKGROUND. Cisplatin-based therapy is standard in patients with advanced urothelial carcinoma but a large proportion are ineligible due to renal impairment. The safety and activity of a dose-dense carboplatin-based regimen in this patient population were explored. METHODS. Patients with advanced urothelial carcinoma who were ineligible for cisplatin were eligible based on at least 1 of the following: 1) serum creatinine >1.5 mg/dL; 2) creatinine clearance of >30 mL/min/1.73 m² and 2; and/or 3) prior nephrectomy. Patients received treatment with doxorubicin plus gemcitabine every other week × 5 cycles followed by paclitaxel plus carboplatin weekly × 12 cycles. RESULTS. Twenty-five patients were treated. Myelosuppression was the major toxicity, with 28% of patients experiencing grade 3–4 neutropenia; there were only 2 (8%) episodes of febrile neutropenia. Grade ≥3 nonhematologic toxicities were infrequent with the exception of grade ≥3 thrombotic episodes in 4 (16%) patients. There were 5 complete responses and 9 partial responses for an overall response rate of 56% (95% confidence interval [CI]: 35%–76%). The median survival was 15 months (95% CI: 11–30). At a median follow-up for survivors of 45 months, 7 (28%) patients are disease-free. CONCLUSIONS. Dose-dense sequential chemotherapy is tolerable and active in patients with urothelial carcinoma and renal impairment. Prolonged disease-free survival is achievable in a subset of patients with primary unresectable disease or lymph-node only metastases treated with carboplatin-based therapy ± surgical consolidation. Randomized trials are needed to define the optimal regimen in patients with advanced urothelial carcinoma and renal impairment. Cancer 2007 © 2007 American Cancer Society.