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The addition of either docetaxel or an androgen receptor signalling pathway inhibitor (ARSi) to androgen-deprivation therapy (ADT) has become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC) patients. Recent phase III data support even greater survival impact of a triplet regimen with ADT plus docetaxel plus an ARSi (abiraterone or darolutamide) compared to ADT plus docetaxel.To evaluate whether the addition of an ARSi to ADT improves outcomes of mCSPC patients treated with docetaxel.We searched MEDLINE/PubMed, the Cochrane Library, and ASCO Meeting abstracts for randomised clinical trials (RCTs) testing the combination of ARSi + ADT in mCSPC men who received docetaxel. Data extraction was conducted according to the PRISMA statement. Summary hazard ratio (HR) was calculated using random- or fixed-effects models. The statistical analyses were performed with RevMan software (v.5.2.3).Five RCTs were selected. Triplet therapy improved overall survival (OS) compared to ADT + docetaxel in mCSPC patients (HR = 0.73; p lt; 0.00001). This intensified strategy maintained the OS benefit when the ARSi was administered concomitant to chemotherapy (HR = 0.72; p lt; 0.00001), but no statistical effect was detected if the ARSi was sequential to docetaxel (p = 0.44). Moreover, in the subgroup of men with de novo mCSPC, triplets significantly improved OS (HR = 0.72, p lt; 0.0001). The lack of access to raw data was the main limit of our analysis.Our results support a clear survival advantage of adding an ARSi to ADT in mCSPC patients treated with docetaxel, mainly when the ARSi was administered concomitantly to chemotherapy and in the subgroup of de novo mCSPC.

BACKGROUND: Enzalutamide combined with androgen deprivation therapy (ADT) significantly prolonged metastasis-free survival and overall survival (OS) versus ADT alone in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with rapidly rising prostate-specific antigen (PSA). The objective of this post hoc analysis of the PROSPER trial is to evaluate OS benefit and safety of enzalutamide in patients across age and regional subgroups. PATIENTS AND METHODS: Eligible men with nmCRPC, PSA doubling time ≤10 months and PSA ≥2 ng/mL with continued ADT use were randomised 2:1 to enzalutamide 160 mg or placebo. OS and safety were examined by age (

Background Tivozanib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 tyrosine kinases. This open-label, crossover clinical study (AV-951-09-902) provided access to tivozanib for patients who progressed on sorafenib in TIVO-1, comparing tivozanib with sorafenib in patients with advanced renal cell carcinoma (RCC). Methods Patients enrolled in this single-arm, phase 2 crossover study were previously randomised to sorafenib on TIVO-1, progressed and then crossed over to tivozanib. Patients received tivozanib (1.5 mg/day orally; 3 weeks on/1 week off) within 4 weeks after their last sorafenib dose. Findings Crossover patients were exposed to tivozanib for a median of eight cycles. From the start of tivozanib treatment, median progression-free survival was 11.0 months (95% confidence interval [CI]: 7.3–12.7) and median overall survival was 21.6 months (95% CI: 17.0–27.6). Best overall response was partial response in 29 (18%) patients and stable disease in 83 (52%) patients, with a median duration of response of 15.2 and 12.7 months, respectively. About 77% of patients experienced adverse events, most frequently hypertension (26%), followed by diarrhoea (14%) and fatigue (13%); 53% of patients had treatment-related adverse events, including 24% grade ≥3. About 9% and 16% of patients had dose reductions and dose interruptions due to adverse events, respectively. A total of 30% of patients had serious adverse events, and 4% had treatment-related serious adverse events. Interpretation This crossover study of patients with advanced RCC demonstrated potent tivozanib anti-tumour activity. Safety and tolerability profiles were acceptable and consistent with the established adverse event profile of tivozanib.

The appropriateness of the numerous therapeutic options available for patients with advanced or metastatic renal cell carcinoma (RCC) was evaluated in 2011, using the RAND/University of California, Los Angeles (UCLA) appropriateness methodology to match treatment suitability to a range of patient scenarios. However, the RCC therapeutic area evolves rapidly and a body of new clinical data has accrued in the intervening years; as a result the exercise was repeated in 2013 using the same methodology, expert panel and patient scenarios. The aim of the updated assessment was to update the guidance to clinicians and use it to develop an interactive web-based application, the Renal Cell Carcinoma Appropriateness-based Treatment Toolkit (ReCATT). This round of assessment achieved greater concordance concerning the appropriateness of treatments/interventions for the clinical scenarios tested; this higher level of agreement is likely to reflect the body of scientific evidence accrued since the previous assessment exercise. Many of the areas of disagreement in 2011 related to the suitability of pazopanib or sunitinib treatment; in the 2013 assessment both agents were considered appropriate treatment options for many of the clinical scenarios assessed. Uncertain scenarios often are related to the optimal management of metastatic RCC with clear cell histology. The use of the RAND/UCLA RCC assessment findings to develop the ReCATT support tool will help to disseminate expert opinion concerning best treatment practice and guide the clinical management of RCC patients treated in the community setting.

Background Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib—a broad-targeted inhibitor of tyrosine kinases, including FGFR3—were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. Methods Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant ( FGFR3 MUT ; n =12), wild-type ( FGFR3 WT ; n =31), or unknown ( n =1) FGFR3 status. Patients received 500mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). Results Most of the patients were men (75%) and over half of the patients were aged ⩾65years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3 MUT (0%; 95% confidence interval [CI], 0.0–26.5) and FGFR3 WT (3.2%; 95% CI, 0.1–16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). Conclusion Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426.

A diverse range of treatment options and interventions are available for the management of renal cell carcinoma (RCC), allowing clinicians to tailor therapy to best meet their patient's needs and situation. However, choosing from the plethora of options can be problematic. RCC treatment guidelines advise on the most efficacious agents based upon specific clinical trial populations, but these do not always take into account all the patient factors that influence the suitability of treatment options for individual patients. This study used the validated RAND/UCLA (RAND corporation/University of California, Los Angeles) 'appropriateness methodology' to integrate clinical efficacy data with expert opinion concerning the use of specific RCC treatment options for particular patient scenarios, in an attempt to facilitate the widespread implementation of patient-focussed treatment choices. Use of the methodology has allowed us to develop treatment algorithms for patients with locally-advanced RCC and for those with metastatic disease post-nephrectomy or with primary tumour in situ. The algorithms take into account patient-specific characteristics such as tumour histology, prior treatment and known risk factors to advise whether a particular treatment intervention is appropriate, not appropriate or of uncertain appropriateness. Use of this methodology aims to develop a formalised process by which expert opinion can be integrated with clinical data and used as an additional source of information that can provide further guidance concerning difficult treatment decisions when data are absent or sparse. (C) 2012 Elsevier Ltd. All rights reserved.

In a double-blind, randomised phase III trial of advanced renal cell carcinoma patients, pazopanib 800mg QD (n=290) versus placebo (n=145) significantly prolonged progression-free survival (hazard ratio (HR)=0.46, 95% confidence interval [CI] 0.34-0.62, p-value0.0001), without important differences in health-related quality of life (HRQoL). This post-hoc analysis evaluated time to HRQoL deterioration and whether tumour response/stabilisation was associated with HRQoL improvement.HRQoL was assessed using EORTC QLQ-C30 and EQ-5D. Effect of pazopanib on time to ⩾20% decline from baseline in summary scores was estimated for all patients and by prior treatment. Analyses were conducted for different HRQoL deterioration thresholds. HRQoL changes were stratified by benefit and compared: complete response (CR) or partial response (PR) versus progressive disease (PD); CR/PR versus stable disease (SD), and SD versus PD.There was a trend for pazopanib patients to be less likely than placebo patients to experience ⩾20% HRQoL deterioration in EORTC-QLQ-C-30 global health status/QOL scale (HR=0.77; 95% CI 0.57-1.03, not significant). Results by prior treatment and different HRQoL deterioration thresholds were similar. Patients with CR/PR and SD experienced significantly less HRQoL deterioration than those with PD (p0.001, p=0.0024, respectively); mean differences between patients with CR/PR and PD exceeded the pre-determined minimally important difference (MID). Differences between patients with SD and PD did not exceed pre-determined MID. Results were generally consistent across treatment and EQ-5D summary scores.Results support the favourable benefit-risk profile of pazopanib and suggest patients experiencing tumour response/stabilisation also may have better HRQoL compared to those without this response.

Expression of epidermal growth factor receptor (EGFR) may be of prognostic value in renal cell cancer (RCC). Gene amplification of EGFR was investigated in a cohort of 315 patients with advanced RCC from a previously reported randomised study. Using fluorescent in situ hybridisation, only 2 patients (0.6%) had gene amplification; therefore gene amplification is of no prognostic value in RCC.

Increased insight into the biology of prostate cancer and the emergence of new therapeutic strategies and chemotherapeutic agents has changed approaches in treating patients with advanced prostate cancer. After secondary hormonal manipulations, new approaches include: second-line hormonal therapy, chemotherapy, immunotherapy with granulocyte macrophage-colony stimulating factor (GM-CSF) therapy, dendritic cell therapy, gene vaccination therapy, inhibition and/or blockade of growth factor receptors or growth factor receptor pathways, inhibition of neo-angiogenesis and inhibition of invasion and metastases.

Muscle-infiltrating bladder cancer should be dealt with in a multimodality approach with collaboration between the urologist, medical oncologist and radiotherapist. Neo-adjuvant chemotherapy has not been proven to improve survival, but may be useful in programs of bladder preservation. Response to M-VAC neo-adjuvant chemotherapy is an important prognostic factor, but may represent patient selection factors. It is not known whether it is better to administer chemotherapy in the neo-adjuvant or in the adjuvant setting, that may spare some patients unnecessary chemotherapy. The international adjuvant chemotherapy trial coordinated by the EORTC (protocol 30994) will hopefully clarify some of the unanswered questions concerning whether or not adjuvant chemotherapy immediately following cystectomy improves survival.

Sixty-five evaluable patients (pts) with locally advanced T2–T4 NOMO TCC of the bladder were treated with 3 cycles of neo-adjuvant M-VAC chemotherapy. 18 (28%) were T2, 22 (34%) were T3a, 21 (33%) were T3b, 4 (6%) were T4a. Pts were restaged clinically by repeat CT scan and TURB, and were to undergo pathologic staging. Partial cystectomy was to be performed in pts with initial monofocal lesions who responded to therapy. As the study evolved, many pts who responded to M-VAC underwent restaging TURB only. 6 pts had 20–30% dose reductions of all the drugs due to age (72 to 80). The median flu is 36 months (range 6 ± 78+ months). 44/65 pts (68%) were managed with conservative therapy (TURB or partial cystectomy). 34/44 (77%) are alive, 28 (64%) with a functional bladder. Pts who had downstaging of their tumors to absence of disease (cT0/pT0) or superficial disease, have 2 and 3-yr survivals of 86% and 83%. For pts with muscle-infiltrating tumors after M-VAC, 2 and 3-yr survivals are 89% and 32%. Response to chemotherapy may be the most important predictor of survival. 28/65 (43%) pts have conserved the bladder. Although bladder conservation is feasible in selected patients, they remain at risk for recurrence.