A B S T R A C T PurposeA randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-␣) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Patients and MethodsSeven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-␣ 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. ResultsMedian overall survival was greater in the sunitinib group than in the IFN-␣ group (26.4 v 21.8 months, respectively; hazard ratio [HR] ϭ 0.821; 95% CI, 0.673 to 1.001; P ϭ .051) per the primary analysis of unstratified log-rank test (P ϭ .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P ϭ .049). Within the IFN-␣ group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-␣ (P Ͻ .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-␣ (P Ͻ .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). ConclusionSunitinib demonstrates longer overall survival compared with IFN-␣ plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.

PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.

SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC.

Purpose Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups. Methods An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations. Results PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials. Conclusion PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

clinicaltrials.gov Identifier: NCT00077974.

Cellular senescence is a response to nonlethal stress that results in persistent cytostasis with a distinct morphological and biochemical phenotype. The senescence phenotype, detected in tumors through the expression of mRNA and protein markers, can be generated in cancer cells lacking functional p53 and retinoblastoma protein. Current research suggests that therapy-induced senescence (TIS) represents a novel functional target that may improve cancer therapy. TIS can be induced in immortal and transformed cancer cells by selected anticancer compounds or radiation, and accumulating data indicate that TIS may produce reduced toxicity-related side effects and increased tumor-specific immune activity. This review examines the current status of TIS-regulated mechanisms, agents, and senescence biomarkers with the goal of encouraging further development of this approach to cancer therapy. Remaining hurdles include the lack of efficient senescence-inducing agents and incomplete biological data on tumor response. The identification of additional compounds and other targeted approaches to senescence induction will further the development of TIS in the clinical treatment of cancer.

Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.