Benoit Baron

Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group.

PURPOSE To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

Comparison of CA-125 and Standard Definitions of Progression of Ovarian Cancer in the Intergroup Trial of Cisplatin and Paclitaxel Versus Cisplatin and Cyclophosphamide

PURPOSE A definition for progression of ovarian cancer has been proposed based on either a confirmed doubling of CA-125 levels from the upper limit of normal or from the nadir level if levels are persistently elevated. Retrospectively, we determined whether the use of this CA-125 definition in a randomized trial would have shown the same magnitude of difference between the treatment arms as was shown when the standard progression definition was used. PATIENTS AND METHODS A retrospective analysis was performed on 680 patients in the Taxol Intergroup Trial with advanced epithelial ovarian carcinoma, of whom 628 were assessable according to CA-125. The date of progression according to clinical or radiologic criteria was compared with the date of progression according to CA-125. RESULTS Of the 628 patients assessable for both definitions, 556 clinical or radiologic progressions were determined compared with 389 according to the CA-125 definition. There was a highly significant difference in the hazard of progression between the paclitaxel and cisplatin arm (TP) compared with the cyclophosphamide and cisplatin arm (CP) when either standard or CA-125 criteria were used to define progression (standard, P = .002; CA-125, P = .011). The hazard ratio of TP/CP over time was similar when comparing the different methods of defining progression. CONCLUSION The results of this analysis show that the magnitude of the therapeutic benefit was similar whether CA-125 or standard criteria were used to define progression.

Cost effectiveness of paclitaxel/cisplatin compared with cyclophosphamide/cisplatin in the treatment of advanced ovarian cancer in Belgium

AbstractObjective: To assess the economic impact of two polychemotherapy regimens for patients with advanced ovarian cancer from the perspective of the Belgian health insurance and financing system. Design: An economic evaluation was integrated in an intergroup randomised controlled trial (EORTC 55931) in which patients were randomised to receive the new treatment of paclitaxel and cisplatin or the standard therapy of cyclophosphamide and cisplatin. Data on the use of medical resources were collected prospectively for the 231 European Organization for Research and Treatment of Cancer (EORTC) patients in the trial and costs were valued by using unit prices. The outcome for the economic evaluation was mean survival time as determined by the so-called restricted means method, with the time point of restriction fixed by statistical criteria. A correction of censoring of the cost data collected in the trial was also performed. Main outcome measures and results: The paclitaxel and cisplatin group experienced a statistically significant improvement in mean survival time of 4 months, which was associated with an increase in the average total cost per patient of 6795 euros (EUR; 1998 values), when costs were assessed over the same period as the gain in mean survival time. This corresponds to a point estimate of the incremental cost-effectiveness ratio of EUR20 385 per life-year gained. The impact of uncertainty was assessed by using a bias-corrected and accelerated bootstrap method with 5000 resamples, and the final results of the analysis are expressed in terms of a cost-effectiveness acceptability curve. Conclusions: The present economic evaluation has shown that the substitution of paclitaxel for cyclophosphamide in the chemotherapy regimen for women with advanced ovarian cancer leads to a significant improvement in patient survival, which is associated with an increase in costs for the Belgian health insurance system.

Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results.

BACKGROUND Enzalutamide is an androgen receptor inhibitor with a demonstrated overall survival benefit in metastatic castration-resistant prostate cancer. A phase 2 study of enzalutamide monotherapy in patients with hormone-naïve prostate cancer (HNPC) showed a high response rate for the prespecified primary endpoint (ie, prostate-specific antigen [PSA] response at week 25), regardless of metastases at baseline, and favorable tolerability. OBJECTIVE To determine the long-term efficacy and safety of enzalutamide monotherapy at 1 and 2 yr. DESIGN, SETTING, AND PARTICIPANTS Open-label, single-arm study in patients with HNPC and noncastrate testosterone (≥230 ng/dl). INTERVENTION Oral enzalutamide 160mg/d until disease progression or unacceptable toxicity. OUTCOME MEASUREMENTS AND ANALYSIS PSA response (≥80% decline from baseline) assessed at 1 yr (49 wk) and 2 yr (97 wk). RESULTS AND LIMITATIONS The median (range) age was 73 (48-86) yr and 26 patients (39%) presented with metastases at study entry. Of 67 patients enrolled, 45 (67%) remained on enzalutamide at week 97. For patients remaining on therapy, the PSA response rate at week 97 was 100% (95% confidence interval 92-100%). Of 26 patients with metastases at baseline, 13 (50%) had a complete and four (15.4%) had a partial response as best overall tumor response up to 97 wk on treatment. There was overall maintenance of total-body bone mineral density (BMD) and moderate changes in lean and fat body mass at 49 and 97 wk. The most common adverse events were gynecomastia, nipple pain, fatigue, and hot flushes. The study limitations include lack of a control group and of endocrine, glycemic, and lipid data at 97 wk. CONCLUSIONS Long-term enzalutamide monotherapy in men with noncastrate HNPC is associated with large sustained reductions in PSA, signals indicating a favorable tumor response, and favorable safety/tolerability profile, with relatively small negative effects on total-body BMD. PATIENT SUMMARY In this long-term follow-up of the efficacy and safety of enzalutamide monotherapy in patients with hormone-naïve prostate cancer, enzalutamide maintained long-term reductions in prostate-specific antigen, with a minimal impact on total-body bone mineral density. TRIAL REGISTRATION NCT01302041.

Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe

BACKGROUND Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. OBJECTIVE To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment. DESIGN, SETTING, AND PARTICIPANTS Multicentre, single-arm, open-label study, enrolled patients with progressing mCRPC after ≥24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required. INTERVENTION Patients received enzalutamide 160mg/d orally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. RESULTS AND LIMITATIONS Overall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naïve. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1-8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6-5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported. CONCLUSIONS Enzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment. PATIENT SUMMARY Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy, received enzalutamide. Although cross-resistance between the two agents was observed in a majority of patients, some still benefited from enzalutamide treatment.

Impact of Enzalutamide Compared with Bicalutamide on Quality of Life in Men with Metastatic Castration-resistant Prostate Cancer: Additional Analyses from the TERRAIN Randomised Clinical Trial

BACKGROUND Improving health-related quality of life (HRQoL) is an important goal in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE To examine the impact of enzalutamide versus bicalutamide on HRQoL in mCRPC. DESIGN, SETTING, AND PARTICIPANTS TERRAIN is a multinational, phase 2, randomised, double-blind study in asymptomatic/mildly symptomatic men with mCRPC (ClinicalTrials.gov, NCT01288911). Patients were randomised (1:1) via an interactive voice and web response system to enzalutamide 160mg/d (n=184) or bicalutamide 50mg/d (n=191), with androgen deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P), European Quality of Life 5-Domain Scale (EQ-5D), and Brief Pain Inventory, Short-form questionnaires every 12 wk. Primary and secondary analyses utilised mixed models for repeated measures and pattern mixture models, respectively. RESULTS AND LIMITATIONS At 61 wk, 84 (46%) enzalutamide and 39 (20%) bicalutamide patients in the study were assessed. At 61 wk, changes from baseline favoured enzalutamide versus bicalutamide on three FACT-P domains in mixed models for repeated measures analyses and seven in pattern mixture models analyses. There were no differences in changes for EQ-5D index/visual analogue scale scores. Risk of first deterioration was lower with enzalutamide for FACT-P total (hazard ratio: 0.64, 95% confidence interval: 0.46-0.89, p=0.007), FACT-G total (hazard ratio: 0.70, 95% confidence interval: 0.50-0.98, p=0.04), PCS pain (hazard ratio: 0.74, 95% confidence interval: 0.54-1.00, p=0.048), and EQ-5D index (hazard ratio: 0.66, 95% confidence interval: 0.47-0.93, p=0.02) scores versus bicalutamide. Brief Pain Inventory, Short-form scores increased in both groups. There was no difference in time-to-pain progression. Study limitations include the exploratory nature of the HRQoL analyses, lack of multiple comparisons corrections, and unknown effects of anxiety/depression on HRQoL. CONCLUSIONS In patients with asymptomatic/mildly symptomatic mCRPC, enzalutamide provides HRQoL benefit versus bicalutamide. PATIENT SUMMARY Enzalutamide treatment was associated with better health-related quality of life in several domains versus bicalutamide in asymptomatic/mildly symptomatic metastatic castration-resistant prostate cancer. This likely relates to previously reported lower rates of symptomatic disease progression.

Efficacy and Safety of Enzalutamide vs Bicalutamide in Younger and Older Patients with Metastatic Castration-resistant Prostate Cancer in the TERRAIN Trial.

Purpose Enzalutamide significantly prolonged median progression‐free survival vs bicalutamide in chemotherapy naïve men with metastatic castration resistant prostate cancer in the TERRAIN (Enzalutamide versus Bicalutamide in Castrate Men with Metastatic Prostate Cancer) trial. In this post hoc analysis we investigated the influence of age on the efficacy and safety of enzalutamide vs bicalutamide in this population. Materials and Methods Patients were randomized 1:1 to enzalutamide 160 mg per day or bicalutamide 50 mg per day. Progression‐free survival, time to prostate specific antigen progression and safety were analyzed post hoc in younger (age less than 75 years) and older (age 75 years or greater) subgroups. Results Enzalutamide significantly reduced the risk of disease progression or death vs bicalutamide in patients younger than 75 years (HR 0.38, 95% CI 0.27–0.52, p <0.0001) and 75 years old or older (HR 0.59, 95% CI 0.37–0.92, p = 0.018). Time to prostate specific antigen progression was also significantly prolonged with enzalutamide vs bicalutamide in each subgroup. The adverse event distribution between treatments was similar in each subgroup except for more (5% or greater difference between subgroups) atrial fibrillation, urinary tract infections, falls and decreased appetite as well as less extremity pain and hot flushing in enzalutamide treated patients 75 years old or older, and less back pain and hot flushing in bicalutamide treated patients 75 years old or older. Grade 3 or greater cardiac events were more frequent in enzalutamide treated and bicalutamide treated patients who were 75 years old or older vs younger than 75 years. Fatigue was more frequent in enzalutamide treated patients with a similar distribution in each age subgroup. Conclusions Enzalutamide improved clinical outcomes vs bicalutamide irrespective of age. Increased falls and cardiac events suggest caution when prescribing to older patients (age 75 years or greater) with significant comorbidity.

Long-Term Antitumor Activity and Safety of Enzalutamide Monotherapy in Hormone Naïve Prostate Cancer: 3-Year Open Label Followup Results

Purpose: A phase 2 study of enzalutamide monotherapy in patients with hormone naïve prostate cancer demonstrated high prostate specific antigen response rates at 25 weeks, 1 year and 2 years with minimal effects on total body bone mineral density and favorable safety. In this followup analysis we evaluated enzalutamide antitumor activity and safety at 3 years. Materials and Methods: In a single arm analysis 67 patients with hormone naïve prostate cancer and noncastrate testosterone (230 ng/dl or greater) received enzalutamide 160 mg per day orally until disease progression or unacceptable toxicity. The primary end point was the prostate specific antigen response (80% or greater decline from baseline). Results: No patients discontinued treatment during year 3. Of 42 patients with prostate specific antigen assessments at 3 years 38 (90.5%, 95% CI 77.4–97.3) maintained a prostate specific antigen response. Of 26 patients with metastases at baseline 17 (65.4%) had a complete or partial response as the best overall response during 3 years. In patients who completed the 3‐year visit minimal mean changes from baseline were observed in total body bone mineral density or bone mineral density of the femoral neck, trochanter, spine L1–L4 or forearm (range –2.7% to –0.1%). At 3 years total body fat had increased a mean of 16.5%, total lean body mass had decreased a mean of –6.5% and global health status had minimally decreased from baseline. Common adverse events were gynecomastia, fatigue, hot flush and nipple pain. Conclusions: Enzalutamide antitumor activity was maintained in patients with hormone naïve prostate cancer at 3 years. Overall bone mineral density, global health status and safety results were similar to those at 2 years.

766PDLONG-TERM EFFICACY AND SAFETY OF ENZALUTAMIDE MONOTHERAPY IN HORMONE-NAIVE PROSTATE CANCER: 2-YEAR FOLLOW-UP

ABSTRACT Aim: Androgen-deprivation therapy (ADT) is the first-choice treatment for advanced prostate cancer (PC). Enzalutamide (ENZ) is approved for the treatment of post-docetaxel metastatic castration-resistant PC. In previous analyses of a Phase 2 study in pts with hormone-naive PC (HNPC) eligible for ADT, ENZ monotherapy after 6 mos and 1 yr (49 wks) was associated with a high prostate-specific antigen (PSA) response rate regardless of presence of metastatic disease at baseline, and with stable bone mineral density (BMD) and quality of life (QoL) on treatment. Here we report long-term efficacy and safety in pts treated up to 2 yrs (wk 97). Methods: 67 patients with HNPC and noncastrate testosterone (≥230 ng/dL) were enrolled in this open-label single-arm study (NCT01302041) and received ENZ 160 mg/d until disease progression or unacceptable toxicity. The primary variable of PSA response (≥80% decline from baseline) was assessed at 6 mos, 1 yr, and 2 yrs. Additional endpoints included best overall objective tumour response, BMD, body composition, QoL and safety. Results: 67 pts were treated. Median age was 73.0 yrs (range 48-86); 26 (38.8%) had metastatic disease at baseline, and 24 (35.8%) and 16 (23.9%) had prior prostatectomy and radiation, respectively. 4 pts discontinued during the second year of follow-up and 45 remained on ENZ at 2 yrs. PSA response rate in pts remaining on ENZ at 2 yrs was 100% (95% CI 92, 100). Of 26 pts with metastases at baseline, 13 (50%) had complete response and 4 (15.4%) partial response as best overall tumour response over 2 yrs. There were decreases in mean (SD) total body BMD of -0.39% (2.24) and lean body mass -5.27% (3.66) at 2 yrs. EORTC-QLQ C30 QoL data showed maintenance of global health status through 2 yrs, though there were clinically meaningful deteriorations (≥10 points) on the fatigue, and role functioning scales. Most common adverse events (AEs) were gynaecomastia, fatigue, nipple pain and hot flush. Conclusions: ENZ monotherapy was associated with significant long-term PSA reductions and good tumour response in men with HNPC. This was achieved without adversely affecting total body BMD or global health status. Disclosure: B. Tombal: has received consultancy fees from Astellas, Medivation, Amgen, and Sanofi Aventis; payment for speaker bureaus from Amgen, Sanofi Aventis, Ferring, and Bayer (for whom he is also a board member); and travel support from Astellas and Medivation; M. Borre: has received payment for speaker bureaus from Astellas and Janssen; is a member of a Medivation study Steering committee and has received consultancy fees from Astellas, Ferring and Sanofi Aventis; P. Rathenborg: has received research grant support paid to his institution from Astellas and Medivation; A. Heidenreich: has received consultancy fees and payment for speaker bureaus from Amgen, Jansen, Ipsen, Sanofi Aventis, and Takeda (for whom he is also a board member); research and travel support from Astellas, and a research grant from Sanofi Aventis; P. Iversen: Research grant support from Astellas and Medivation; travel support for meetings related to the study from Astellas and Medivation; honoraria from Astellas and Medivation; and consultancy fees from Janssen, Ferring and Sanofi-Aventis; J. Braeckman: has received payment for speaker bureaus from Amgen and Eli Lilly; E. Baskin-Bey, T. Ouatas, F.G. Perabo, D. Phung and B. Baron: Employee of Astellas; M. Hirmand: is an employee of Medivation and owns stock in Medivation; M.R. Smith: has received consultancy fees from Astellas, Medivation, Janssen, Aragon, and Millenium. All other authors have declared no conflicts of interest.