Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.

BACKGROUND: The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. METHODS: ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0-2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. FINDINGS: Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63-74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67-69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58-0·84]; p<0·0001), with 5-year overall survival of 57% (0·53-0·61) in the control group and 67% (0·63-0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1-3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. INTERPRETATION: The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. FUNDING: Astellas Pharma.

Attitudes towards open-label versus placebo-control designs in oncology randomized trials: A survey of medical oncologists.

RATIONALE, AIMS AND OBJECTIVES: Randomized trials are considered the gold standard when assessing the efficacy of new therapeutic agents. In clinical situations where no standard of care therapy is approved, randomized trials usually compare experimental agents to either a placebo or an open-label nonintervention arm (i.e., best supportive care). We surveyed Canadian medical oncologists to understand their attitudes towards each design. METHODS: Members of the Canadian Association of Medical Oncologists were invited to participate in an anonymous online survey. Standardized case scenarios were used to determine participants' attitudes regarding the role of open-label versus placebo-controlled trials. RESULTS: A total of 322 medical oncologists and trainees were invited to participate and 86 responded (response rate 27%). Fifty-one (59%) believed that open-label trials are an acceptable alternative to placebo-controlled design when investigating a therapeutic agent in the adjuvant setting. Thirty-eight (49%) deemed it acceptable to compare the investigational agent to an open-label arm instead of a placebo to assess progression-free survival in the metastatic setting. Twenty-eight (38%) of respondents felt that open-label design was acceptable when assessing the quality of life endpoint. Most physicians were unsure whether the US Food and Drug Administration require a placebo-controlled arm in oncology trials. CONCLUSION: Canadian medical oncologists participating in this survey are divided in their opinions regarding the acceptability of an open-label design in randomized-controlled trials, where no standard therapy is approved. Clearer guidance from regulatory bodies on the adequacy of different trial designs is needed.

Utilization and Safety of Ipilimumab Plus Nivolumab in a Real-World Cohort of Metastatic Renal Cell Carcinoma Patients.

INTRODUCTION: Ipilimumab plus nivolumab was associated with a survival benefit in a phase III clinical trial of first-line treatment for metastatic renal cell carcinoma (mRCC). In this study, mRCC patients from the Canadian Kidney Cancer Information System (CKCis) database who received first-line ipilimumab plus nivolumab were analyzed to determine the safety and outcomes in a real-world setting. PATIENTS AND METHODS: Patients who received ipilimumab plus nivolumab as first-line therapy for mRCC in CKCis, were identified, and the amount of treatment received, discontinuation rates, and reasons for discontinuing treatment were determined. Toxicity data, including type and grade, were collected. Efficacy outcomes of interest included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: The cohort included 195 patients, the majority with clear cell histology (74%). All 4 cycles of ipilimumab plus nivolumab were administered in 124 patients (64%). Progressive disease (n = 87; 45%) and toxicity (n = 36; 18%) were the most common causes for discontinuing treatment. Several patients (n = 18) did not receive all 4 doses of ipilimumab but received single agent nivolumab. The estimated median OS was 54.5 months (95% CI, 17.7 - NE) and 12-month OS was 72.2% (95% CI, 65.0 - 79.3). Median PFS was 7.4 months (95% CI 5.3 - 10.2) and ORR was 42.5%. Patients who received all 4 cycles of ipilimumab plus nivolumab had better ORR (50% vs. 28%) and a longer PFS and OS than those who received less than 4 cycles (P < .0001). Ninety-five AEs were documented in 72 patients who required dose reduction/change, with colitis being the most frequent. CONCLUSION: In this real-world cohort of treatment-naïve mRCC patients, outcomes, and safety were comparable to previously reported clinical trial data.

The need for speed in advanced non-small cell lung cancer: A population kinetics assessment.

BACKGROUND: Systemic therapy prolongs overall survival (OS) in advanced non-small cell lung cancer (NSCLC), but diagnostic tests, staging and molecular profiling take time, and this can delay therapy initiation. OS approximates first-order kinetics. METHODS: We used OS of chemo-naive NSCLC patients on a placebo/best supportive care trial arm to estimate % of patients dying while awaiting therapy. We digitized survival curves from eight studies, calculated OS half-life, then estimated the proportion surviving after different times of interest (tn ) using the formula: X=exp-tn∗0.693/t1/2 , where EXP signifies exponential, * indicates multiplication, 0.693 is the natural log of 2, and t1/2 is the survival half-life in weeks. RESULTS: Across trials, the OS half-life for placebo/best supportive care in previously untreated NSCLC was 19.5 weeks. Hence, based on calculations using the formula above, if therapy were delayed by 1, 2, 3, or 4 weeks then 4%, 7%, 10%, and 13% of all patients, respectively, would die while awaiting treatment. Others would become too sick to consider therapy even if still alive. CONCLUSIONS: This quantifies why rapid baseline testing and prompt therapy initiation are important in advanced NSCLC. It also illustrates why screening procedures for clinical trial inclusion must be faster. Otherwise, it is potentially hazardous for a patient to be considered for a trial due to risk of death or deterioration while awaiting eligibility assessment. It is also important to not delay initiation of systemic therapy for procedures that add relatively little value, such as radiotherapy for small, asymptomatic brain metastases.

Cost-utility of Sunitinib Versus Pazopanib in Metastatic Renal Cell Carcinoma in Canada using Real-world Evidence.

BACKGROUND AND OBJECTIVE: The development of new targeted therapies in kidney cancer has shaped disease management in the metastatic phase. Our study aims to conduct a cost-utility analysis of sunitinib versus pazopanib in first-line setting in Canada for metastatic renal cell carcinoma (mRCC) patients using real-world data. METHODS: A Markov model with Monte-Carlo microsimulations was developed to estimate the clinical and economic outcomes of patients treated in first-line with sunitinib versus pazopanib. Transition probabilities were estimated using observational data from a Canadian database where real-life clinical practice was captured. The costs of therapies, disease progression, and management of adverse events were included in the model in Canadian dollars ($Can). Utility and disutility values were included for each health state. Incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratios (ICER) were calculated for a time horizon of 5 years, from the Canadian Healthcare System perspective. RESULTS: The cost difference was $36,303 and the difference in quality-adjusted life year (QALY) was 0.54 in favour of sunitinib with an ICUR of $67,227/QALY for sunitinib versus pazopanib. The major cost component (56%) is related to best supportive care (BSC) where patients tend to stay for a longer period of time compared to other states. The difference in life years gained (LYG) between sunitinib and pazopanib was 1.21 LYG (33.51 vs 19.03 months) and the ICER was $30,002/LYG. Sensitivity analysis demonstrated the robustness of the model with a high probability of sunitinib being a cost-effective option when compared to pazopanib. CONCLUSION: When using real-world evidence, sunitinib is found to be a cost-effective treatment compared to pazopanib in mRCC patients in Canada.

Economic evaluation of erythropoiesis-stimulating agents for anemia related to cancer.

BACKGROUND: Erythropoiesis-stimulating agents (ESA) administered to cancer patients with anemia reduce the need for blood transfusions and improve quality-of-life (QOL). Concerns about toxicity have led to more restrictive recommendations for ESA use; however, the incremental costs and benefits of such a strategy are unknown. METHODS: The authors created a decision model to examine the costs and consequences of ESA use in patients with anemia and cancer from the perspective of the Canadian public healthcare system. Model inputs were informed by a recent systematic review. Extensive sensitivity analyses and scenario analysis rigorously assessed QOL benefits and more conservative ESA administration practices (initial hemoglobin [Hb] <10 g/dL, target Hb < or =12 g/dL, and chemotherapy induced anemia only). RESULTS: Compared with supportive transfusions only, conventional ESA treatment was associated with an incremental cost per quality-adjusted life year (QALY) gained of $267,000 during a 15-week time frame. During a 1.3-year time horizon, ESA was associated with higher costs and worse clinical outcomes. In scenarios where multiple assumptions regarding QOL all favored ESA, the lowest incremental cost per QALY gained was $126,000. Analyses simulating the use of ESA in accordance with recently issued guidelines resulted in incremental cost per QALY gained of > $100,000 or ESA being dominated (greater costs with lower benefit) in the majority of the scenarios, although greater variability in the cost-utility ratio was present. CONCLUSIONS: Use of ESA for anemia related to cancer is associated with incremental cost-effectiveness ratios that are not economically attractive, even when used in a conservative fashion recommended by current guidelines.