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In the phase III randomized ALSYMPCA trial of radium-223 in patients with castration-resistant prostate cancer and bone metastases, improved survival with radium-223 is accompanied by significant quality of life benefits, measured by EQ-5D and FACT-P, including a higher percentage of patients with meaningful improvement in quality of life and a slower decline in quality of life over time., Background Radium-223 dichloride (radium-223), a first-in-class α-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase III ALSYMPCA study. ALSYMPCA included prospective measurements of health-related quality of life (QOL) using two validated instruments: the general EuroQoL 5D (EQ-5D) and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P). Patients and methods Analyses were conducted to determine treatment effects of radium-223 plus standard of care (SOC) versus placebo plus SOC on QOL using FACT-P and EQ-5D. Outcomes assessed were percentage of patients experiencing improvement, percentage of patients experiencing worsening, and mean QOL scores during the study. Results Analyses were carried out on the intent-to-treat population of patients randomized to receive radium-223 (n = 614) or placebo (n = 307). The mean baseline EQ-5D utility and FACT-P total scores were similar between treatment groups. A significantly higher percentage of patients receiving radium-223 experienced meaningful improvement in EQ-5D utility score on treatment versus placebo {29.2% versus 18.5%, respectively; P = 0.004; odds ratio (OR) = 1.82 [95% confidence interval (CI) 1.21–2.74]}. Findings were similar for FACT-P total score [24.6% versus 16.1%, respectively; P = 0.020; OR = 1.70 (95% CI 1.08–2.65)]. A lower percentage of patients receiving radium-223 experienced meaningful worsening versus placebo measured by EQ-5D utility score and FACT-P total score. Prior docetaxel use and current bisphosphonate use did not affect these findings. Treatment was a significant predictor of EQ-5D utility score, with radium-223 associated with higher scores versus placebo (0.56 versus 0.50, respectively; P = 0.002). Findings were similar for FACT-P total score (99.08 versus 95.22, respectively; P = 0.004). Conclusions QOL data from ALSYMPCA demonstrated that improved survival with radium-223 is accompanied by significant QOL benefits, including a higher percentage of patients with meaningful QOL improvement and a slower decline in QOL over time in patients with CRPC.

Background Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however,>30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR¼3.21 (1.35–7.67); P¼0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR¼2.71 (1.11–6.63); P¼0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR¼3.23 (1.22–8.59); P¼0.019] whilst CAPRA itself was not significant [HR¼1.88, (0.52–6.77); P¼0.332]. A high concordance [100% (61.5–100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

Background This study describes a repeated measures prediction index to identify patients at high risk of ≥ grade 2 hand-foot skin reaction (HFSR) before each week of sorafenib therapy. Methods Data from 451 patients who received a sorafenib (400 mg bid) as part of a clinical trial were reviewed (Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–134). Generalized estimating equations were used to develop the final risk model. A risk-scoring algorithm (range 0–58) was then derived from the final model coefficients. External validation was then carried out on a new sample of 1145 patients who received sorafenib under an expanded access program. Results Pretreatment white blood cell count, female gender, good performance status, presence of lung and liver metastases and number of affected organs were predictors for ≥ grade 2 HFSR. A nonlinear association between HFSR risk and treatment duration was also identified where risk was maximized at week 5 followed by a gradual decline. Before each week of therapy, patients with risk scores >40 would be considered at high risk for developing ≥ grade 2 HFSR. Conclusions The application and planned continued refinement of this prediction tool will be an important source of patient-specific risk information for the development of moderate to severe HFSR.

Background There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. Methods We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). Results In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74–9.10; P A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47–not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94–9.68; P

Background The safety and efficacy of upfront sunitinib, before nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated. Methods Two prospective single-arm phase II studies investigated either two cycles (study A: n = 19) or three cycles (study B: n = 33) of sunitinib before nephrectomy in mCRC. Results Overall, 38 of 52 (73%) of patients obtained clinical benefit (by RECIST) before surgery. The partial response rate of the primary tumour was 6% [median reduction in longest diameter of 12% (range 8%-35%)]. No patients became ineligible due to local progression of disease. A nephrectomy was carried out in 37 (71%) of patients. Necrosis (>50%) was a prominent feature at nephrectomy in 49%. Surgical complications (Clavien–Dindo classification) occurred in 10 (27%) patients, including one death (3%). The median blood loss and surgical time were 725 (90–4200) ml and 189 (70–420) min, respectively. The median progression-free survival was 8 months (95% confidence interval 6–15 months). A comparison of two versus three pre-surgery cycles showed no significant difference in terms of surgical complications or efficacy. Conclusions Nephrectomy after upfront sunitinib can be carried out safely. It obtains control of disease. Randomised studies are required to address if this approach is beneficial.

Background RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. Patients and methods Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. Results At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1–26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0–29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9–1.6]. Median OS was 22.4 months (95% CI 18.6–33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8–33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9–1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. Conclusions Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. Clinical Trials number ClinicalTrials.gov identifier, NCT00903175

Background This study assessed the human epidermal growth factor receptor-2 (HER2) protein expression and its relationship with gene amplification in invasive bladder carcinoma, using the same criteria than for breast cancer. Patients and methods In 1005 patients, paraffin-embedded tissues of transurethral resection or cystectomy were evaluated by immunohistochemistry (IHC), using antibodies against HER2. All samples with a 2+ or 3+ HER2 overexpression were evaluated by FISH. Results HER2 overexpression was observed in 93 (9.2%) tumors (2+: 42 tumors and 3+: 51 tumors). Using FISH, all HER2 3+ tumors had a gene amplification, whereas no amplification was found in 2+ tumors. Intratumoral heterogeneity was observed in 35% of cases. These tumors showed the same heterogeneous pattern, with adjacent 3+ positive and negative areas by both IHC and FISH. Conclusions This study showed that 5.1% of invasive bladder carcinomas had a HER2 gene amplification. These findings may have clinical implications for the management of patients with HER2-positive locally advanced or metastatic bladder cancer, as they could be potential candidates for targeted therapy.

Background: The purpose of this study is to evaluate the impact on the health-related quality of life (HRQoL) of sunitinib versus interferon-alpha (IFN-α) treatment in patients with metastatic renal cell carcinoma (mRCC). Patients and methods: In all, 304 mRCC patients (European cohort) were randomized 1 : 1 to receive sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off) or IFN-α (9 million units s.c. injection three times/week). The following questionnaires were completed (days 1 and 28 per cycle): Functional Assessment of Cancer Therapy-General (FACT-G), the FACT-Kidney Symptom Index and the EuroQol Group's EQ-5D self-report questionnaire (EQ-5D). Results correspond to an ongoing trial with progression-free survival time as primary end point, and patients were still being followed up. Data were analyzed using repeated measures mixed effects models (MEMs) that allow the inclusion of initial differences and uncompleted repeated measures, with the assumption of data missing at random. Six-cycle results were included. Results: Results consistently showed that patients in sunitinib group experienced statistically significantly milder kidney-related symptoms, better cancer-specific HRQoL and general health status (in social utility scores) during the study period as measured by these patient-reported outcome end points. No statistical differences between groups were found on the FACT-G physical well-being subscale or the EQ-5D VAS values. Conclusions: Results from MEM showed the sunitinib's benefit on HRQoL compared with IFN-α.