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.
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.
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.
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.
Astellas Pharma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PurposeThe purpose of this study was to develop a national program for Canadian diagnostic laboratories to compare DNA-variant interpretations and resolve discordant-variant classifications using the ...BRCA1 and BRCA2 genes as a case study.MethodsBRCA1 and BRCA2 variant data were uploaded and shared through the Canadian Open Genetics Repository (COGR; http://www.opengenetics.ca). A total of 5,554 variant observations were submitted; classification differences were identified and comparison reports were sent to participating laboratories. Each site had the opportunity to reclassify variants. The data were analyzed before and after the comparison report process to track concordant- or discordant-variant classifications by three different models.ResultsVariant-discordance rates varied by classification model: 38.9% of variants were discordant when using a five-tier model, 26.7% with a three-tier model, and 5.0% with a two-tier model. After the comparison report process, the proportion of discordant variants dropped to 30.7% with the five-tier model, to 14.2% with the three-tier model, and to 0.9% using the two-tier model.ConclusionWe present a Canadian interinstitutional quality improvement program for DNA-variant interpretations. Sharing of variant knowledge by clinical diagnostic laboratories will allow clinicians and patients to make more informed decisions and lead to better patient outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: In recent years, patients have indicated a desire for more information about their disease and to be involved in making decisions about their care. We developed an aid called the ...“Decision Board” to help clinicians inform patients with lymph node-negative breast cancer of the risks and benefits of adjuvant chemotherapy. We determined whether adding the Decision Board to the medical consultation improved patient knowledge and satisfaction compared with the medical consultation alone. Methods: Between October 1995 and March 2000, 176 women with lymph node-negative breast cancer who were candidates for adjuvant chemotherapy were randomly assigned to receive the Decision Board plus the medical consultation (83 patients) or the medical consultation alone (93 patients). One week after the consultation, patients completed a questionnaire assessing their knowledge about breast cancer and chemotherapy. Satisfaction with decision making was assessed 1 week and 3, 6, and 12 months after randomization, and differences between groups were analyzed by a repeated measures analysis of variance. All statistical tests were two-sided. Results: Patients in the Decision Board arm were better informed about breast cancer and adjuvant chemotherapy than patients in the control arm (mean knowledge score = 80.2 on a scale of 0–100, 95% confidence interval CI = 77.1 to 83.3, and 71.7, 95% CI = 69.0 to 74.4, respectively; P<.001). Over the entire study period, satisfaction with decision making was higher for patients in the Decision Board arm than for patients in the control arm (P = .032). There was no statistically significant difference between the two groups in the number of patients who chose adjuvant chemotherapy (77% and 70% for patients in the Decision Board arm and those in the control arm, respectively; P = .303). Conclusion: When making decisions regarding adjuvant chemotherapy, patients with early breast cancer who had been exposed to the Decision Board had better knowledge of the disease and treatment options and greater satisfaction with their decision making than those who received the standard consultation.
The Canadian Open Genetics Repository is a collaborative effort for the collection, storage, sharing and robust analysis of variants reported by medical diagnostics laboratories across Canada. As ...clinical laboratories adopt modern genomics technologies, the need for this type of collaborative framework is increasingly important.
A survey to assess existing protocols for variant classification and reporting was delivered to clinical genetics laboratories across Canada. Based on feedback from this survey, a variant assessment tool was made available to all laboratories. Each participating laboratory was provided with an instance of GeneInsight, a software featuring versioning and approval processes for variant assessments and interpretations and allowing for variant data to be shared between instances. Guidelines were established for sharing data among clinical laboratories and in the final outreach phase, data will be made readily available to patient advocacy groups for general use.
The survey demonstrated the need for improved standardisation and data sharing across the country. A variant assessment template was made available to the community to aid with standardisation. Instances of the GeneInsight tool were provided to clinical diagnostic laboratories across Canada for the purpose of uploading, transferring, accessing and sharing variant data.
As an ongoing endeavour and a permanent resource, the Canadian Open Genetics Repository aims to serve as a focal point for the collaboration of Canadian laboratories with other countries in the development of tools that take full advantage of laboratory data in diagnosing, managing and treating genetic diseases.
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Background: BOLERO-2, a phase III study, randomized 724 patients with hormone-receptor–positive metastatic breast cancer, who had recurrence or progression on/after prior ...nonsteroidal aromatase inhibitor therapy, to everolimus (EVE) + exemestane (EXE) or EXE + placebo. A preplanned 12-mo median time interim analysis demonstrated that EVE + EXE significantly improved progression-free survival (PFS) vs EXE + placebo, but EVE + EXE resulted in a higher rate of grade 3-4 toxicity. Per-protocol patients reported HRQoL data are limited; here we report on additional post hoc analyses of these outcomes. Methods: Using the EORTC QLQ-C30 questionnaire, HRQoL was assessed at baseline and every 6 weeks thereafter until progression. QLQ-C30 consists of 30 items combined into 15 subscales, including a Global Health Status (GHS), where higher scores (range, 0-100) indicate better HRQoL. Analysis included a protocol-specified time to definitive deterioration (TTD) analysis at a 5% decrease in QoL relative to baseline, with no subsequent increase above this threshold. We report additional sensitivity analyses using 10-point minimally important difference (MID) decreases in QLQ-C30 score relative to baseline. Treatment arms were compared using a stratified log-rank test and a Cox proportional hazards model adjusted for trial stratum (visceral metastases and previous hormone sensitivity), age, sex, race, baseline score, ECOG performance status, prognostic risk factors, and treatment history. Results: Baseline QLQ-C30 GHS scores were not statistically significantly different across treatment groups (64.7 vs 65.3; difference –0.7 95% CI, –4.3-3.0). Median TTD in HRQoL was 7.0 mo (95% CI, 5.6-8.3) for EVE + EXE vs 5.6 (95% CI, 4.2-7.0) for EXE (p = .0792). Adjusted HR (0.80) approached significance (95% CI, 0.63-1.02). At the 10-point MID, median TTD for EVE + EXE was 9.7 mo (95% CI, 8.3-11.2) vs 8.4 mo (95% CI, 6.3-12.5) for EXE. Adjusted HR was 0.90 (95% CI, 0.69-1.18). Conclusions: These additional analyses from the BOLERO-2 study demonstrate that in addition to significantly improving PFS, EVE + EXE does not compromise HRQoL.
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Background: The phase III BOLERO-2 study at 18 months’ median follow-up showed that everolimus (EVE) + exemestane (EXE) significantly improved progression-free survival (PFS) vs EXE ...alone in 724 patients with hormone receptor–positive (HR+) advanced breast cancer (ABC) with recurrence/progression during/after nonsteroidal aromatase inhibitor (NSAI) therapy. A higher rate of grade 3/4 adverse events was noted with EVE + EXE but was not associated with deterioration in quality of life (QOL) based on the EORTC QLQ-C30 Global Health Status scale. Additional patient-reported post hoc analyses of QOL are reported herein. Methods: During BOLERO-2, QOL (EORTC QLQ-C30 and QLQ-BR23) was assessed at baseline and q 6 wk thereafter until progression or discontinuation. Physical, emotional, and social functioning subscales of QLQ-C30 were analyzed. Time to definitive deterioration (TTD) was defined based on either a 5% (protocol-specified) or a 10-point (more stringent) decrease from baseline for each subscale and analyzed by Kaplan-Meier methods. The difference between treatments was assessed by a log-rank test stratified by randomization factors. Results: QLQ-C30 compliance was >80% at week 48. Among the 3 protocol-specified QLQ-C30 subscales, analyses based on a 5% decrease in QOL showed a longer TTD for both physical and emotional functioning in the EVE + EXE group vs EXE alone (log-rank p = 0.0120 and p = 0.0277, respectively). The TTDs for social functioning were similar in both treatment arms (log-rank p = 0.3374). Analyses based on a 10-point decrease indicated a longer TTD for physical functioning in the EVE + EXE group (15.2 mo) vs EXE alone (9.7 mo; log-rank p = 0.0211). The TTDs for emotional and social functioning were similar between EVE + EXE and EXE alone: 13.9 vs 13.8, respectively (log-rank p = 0.4023), and 11.5 vs 9.5, respectively (log-rank p = 0.2507). Conclusions: The treatment goal for ABC is to maximize clinical benefit with minimal negative effects on QOL. These additional BOLERO-2 QOL analyses confirmed that the more than doubling of PFS with EVE + EXE was accompanied by maintained physical, emotional, and social functioning compared with EXE alone in patients with HR+ ABC progressing after NSAI. Clinical trial information: NCT00863655.
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Background: In BOLERO-2, adding everolimus (EVE) to exemestane (EXE) more than doubled progression-free survival without affecting quality of life vs EXE alone in postmenopausal ...women with hormone-receptor–positive advanced breast cancer who had recurrence or progression on/after nonsteroidal aromatase inhibitor therapy. Although mTOR inhibitors are generally well tolerated, stomatitis is one of their most clinically relevant and potentially dose-limiting toxicities (Sonis Cancer2010). The incidence, grade, and clinical course of stomatitis among patients (pts) participating in the BOLERO-2 study are described. Methods: Pts were randomized 2:1 to receive EVE+EXE or placebo (PBO)+EXE. Stomatitis incidence, severity, consequent dose interruptions/adjustments, study drug discontinuations, and time to resolution were recorded. Results: The median duration of EVE+EXE treatment exposure was 30 wk (range, 1-123 wk). Stomatitis (any grade) occurred more frequently with EVE+EXE than with PBO+EXE (59% vs 12%, respectively). Grade 3 stomatitis occurred in 8% vs 1% of pts receiving EVE+EXE vs PBO+EXE, respectively; no grade 4 was reported. Onset of grade ≥2 stomatitis after treatment initiation was earlier in the EVE+EXE arm vs the PBO+EXE arm: median time was 15d vs 24d, respectively. In the EVE+EXE arm, 97% of pts with grade 3 stomatitis (n=38) improved to ≤1 after a median of 13 d. Complete resolution was observed in 82% of these pts after a median of 38 d. In the PBO+EXE arm, all pts with grade 3 stomatitis (n=2) improved to ≤1 after a median of 18 d. Complete resolution was observed after a median of 29 d. Overall, 24% of pts in the EVE+EXE arm required dose interruptions/adjustments vs 1% of pts in the PBO+EXE arm, and 3% of pts (n=13) discontinued EVE+EXE vs <1% of pts (n=1) discontinuing PBO+EXE, all related to stomatitis. Conclusions: The BOLERO-2 data foster a new era of combining targeted and endocrine therapies. In the study, treatment-emergent stomatitis was of mild to moderate intensity, occurred shortly after treatment initiation, and was generally reversible. Most incidents were successfully managed with palliative interventions and temporary dose modifications. Oral hygiene and other preventive measures are recommended. Clinical trial information: NCT00863655.
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