Dataset Information

Enzalutamide Versus Abiraterone plus Prednisolone Before Chemotherapy for Castration-resistant Prostate Cancer: A Multicenter Randomized Controlled Trial.

ABSTRACT:

Background

Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) improve survival in castration-resistant prostate cancer (CRPC). However, which agent is better for patients with CRPC remains unclear.

Objective

To evaluate whether ENZ or ABI is better as first-line treatment for CRPC.

Design setting and participants

An investigator-initiated, multicenter, randomized controlled trial was conducted in Japan. The study enrolled 203 patients with CRPC before chemotherapy between February 20, 2015, and July 31, 2019. Patients were randomly assigned 1:1 to the ENZ or ABI arm.

Outcome measurements and statistical analysis

The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included the PSA response rate (≥50% decline from baseline), overall survival, and safety. A log-rank test was used for comparison of survival analyses between arms.

Results and limitations

After randomization, 92 patients in each arm were treated and analyzed. Time to PSA progression did not significantly differ between the arms (median 21.2 mo for ENZ and 11.9 mo for ABI; hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.51-1.27; p = 0.1732). There was a significant difference in the PSA response rate between the arms (72% for ENZ and 57% for ABI; p = 0.0425). There was no significant difference in overall survival (median 32.9 mo for ENZA and 35.5 mo for ABI; HR 1.17, 95% CI 0.72-1.88; p = 0.5290). Grade ≥3 adverse events were observed in 11% of patients in the ENZA arm and 21% in the ABI arm (p = 0.1044).

Conclusions

ENZ did not show any survival benefit in comparison to ABI, but showed a better PSA response rate with a low rate of severe adverse events in CRPC.

Patient summary

Results from our study suggest that use of enzalutamide before abiraterone may have potential clinical benefits for patients with castration-resistant prostate cancer.

SUBMITTER: Izumi K

PROVIDER: S-EPMC9257638 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionProstate cancer (PC) is the second leading cause of cancer death among US men and accounts for considerable healthcare expenditures. We evaluated economic outcomes in men with chemotherapy-naïve metastatic castration-resistant PC (mCRPC) treated with enzalutamide or abiraterone acetate plus prednisone (abiraterone).MethodsWe performed a retrospective analysis on 3174 men (18 years or older) utilizing the Veterans Health Administration (VHA) database from 1 April 2014 to 31 March 2018. Men with mCRPC were included if they had at least one pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following surgical or medical castration, had no chemotherapy treatment within 12 months prior to the index date, and had continuous VHA enrollment for at least 12 months pre- and post-index date. Men were followed until death, disenrollment, or end of study and were 1:1 propensity score matched (PSM). All-cause and PC-related resource use and costs per patient per month (PPPM) in the 12 months post index were compared between matched cohorts.ResultsWe identified 1229 men with mCRPC prescribed enzalutamide and 1945 prescribed abiraterone with mean ages of 74 and 73 years, respectively. After PSM, each cohort had 1160 patients. The enzalutamide cohort had fewer all-cause (2.51 vs 2.86; p < 0.0001) and PC-related outpatient visits (0.86 vs 1.03; p < 0.0001), with corresponding lower all-cause ($2588 vs $3115; p < 0.0001) and PC-related ($1356 vs $1775; p < 0.0001) PPPM outpatient costs compared with the abiraterone cohort. All-cause total costs (medical and pharmacy) PPPM ($8085 vs $9092; p = 0.0002) and PC-related total costs PPPM ($6321 vs $7280; p < 0.0001) were significantly lower in the enzalutamide cohort compared with the abiraterone cohort.ConclusionsEnzalutamide-treated men with chemotherapy-naïve mCRPC had significantly lower resource utilization and healthcare costs compared with abiraterone-treated men.

Project description:ObjectiveEvaluation of the comparative effectiveness of enzalutamide and abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) is limited to meta-analyses of randomized trials that exclude patients with significant comorbidities. We evaluated overall survival (OS) in patients with chemotherapy-naive mCRPC treated with enzalutamide or abiraterone acetate (abiraterone) in a real-world single payer setting.MethodsA retrospective analysis (4/1/2014-3/31/2018) of the Veterans Health Administration (VHA) database was conducted. Patients with mCRPC had ≥1 pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following disease progression on surgical/medical castration, without chemotherapy <12 months prior to index date. Patients had continuous VHA enrollment for ≥12 months pre-index date and were followed until death, disenrollment, or end of study. Kaplan-Meier analysis and multivariable Cox proportional hazards regression models examined the OS treatment effect.ResultsPatients with chemotherapy-naive mCRPC (N = 3174; enzalutamide, n = 1229; abiraterone, n = 1945) had mean ages of 74 and 73 years, respectively. Median follow-up was 18.27 and 19.07 months with enzalutamide and abiraterone, respectively. Enzalutamide-treated patients had longer median treatment duration than abiraterone-treated patients (9.93 vs 8.47 months, respectively, p = 0.0008). After baseline comorbidity adjustment, enzalutamide-treated patients had a 16% reduced risk of death (hazard ratio [HR] = 0.84; 95% CI, 0.76-0.94; p = 0.0012). For patients who remained on first line-therapy only, enzalutamide-treated patients had improved OS versus abiraterone-treated patients (HR = 0.71; 95% CI, 0.62-0.82). Enzalutamide-treated patients who crossed over to abiraterone had a comparable risk of death versus abiraterone-treated patients who crossed over to enzalutamide (HR = 1.10; 95% CI, 0.89-1.35). These results were confirmed by sensitivity analysis, which considered prognostic variables.ConclusionsRetrospective analysis of the VHA database indicated that chemotherapy-naive patients with mCRPC initiating therapy with enzalutamide had improved survival versus abiraterone.

Project description:INTRODUCTION:Enzalutamide and abiraterone acetate plus prednisolone (AAP) are used in combination with androgen-deprivation therapy to further suppress the androgen stimulation of metastatic castration-resistant prostate cancer (mCRPC). First-line mCRPC treatment with enzalutamide and AAP yields similar overall survival and radiographic progression-free survival in phase III trials. Thus, treatment selection relies on patient choice, cost and side effects. The aim of this randomised trial is to investigate differences in fatigue, health-related quality of life (HRQoL) and metabolic side effects in men with mCRPC treated with first-line enzalutamide versus AAP. METHODS AND ANALYSIS:In this ongoing open-label randomised (1:1) clinical trial, enzalutamide is compared with AAP as first-line treatment for men with mCRPC. The primary endpoint is fatigue assessed with the questionnaire Functional Assessment of Chronic Illness Therapy-Fatigue version 4. Secondary endpoints are changes in body composition (ie, fat mass, visceral adipose tissue, subcutaneous adipose tissue and lean body mass assessed with dual energy X-ray absorptiometry), glucose metabolism assessed with a 2-hour oral glucose tolerance test, serum lipids, blood pressure and HRQoL assessed with the questionnaire Functional Assessment of Cancer Therapy-Prostate (FACT-P). All study endpoints are assessed at baseline and 12-week postintervention. Blood and urine samples are collected at baseline and at time of progression on allocated treatment for future investigation of predictive and prognostic biomarkers in prostate cancer treatment. The planned sample size is 170 participants. All participants are recruited from Herlev and Gentofte Hospital, Denmark. Estimated last patient's last visit is February 2020. ETHICS AND DISSEMINATION:The study received project approval from the National Committee on Health Research Ethics and Danish Data Protection Agency and Danish Medicines Agency (EudraCT no.: 2017-000027-99). The results of the study will be published in peer-reviewed international journals and will be presented at national and international conferences and symposiums. TRIAL REGISTRATION NUMBER:Clinicaltrialsregister.eu (2017-000099-27).

Project description:BACKGROUND:It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone. OBJECTIVE:To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC). DESIGN, SETTING, AND PARTICIPANTS:This open-label, single-centre interventional study was conducted in bmCRPC patients. INTERVENTION:Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and Cmin plasma concentrations were evaluated. RESULTS AND LIMITATIONS:Sixty patients were enrolled. Common AEs independent of grade/causality included fatigue (72%), hyperglycaemia (67%), alkaline phosphatase (ALP) elevation (53%), and hot flush (43%). Grade 3 AEs included hypertension (17%), alanine aminotransferase elevation (12%), ALP elevation (5%), and arthralgia (5%). No treatment-related grade 4 AEs or deaths were reported. Median treatment-discontinuation time was 312d (95% confidence interval [CI] 196.0-483.0). Maximal PSA decline ?50% and ?90% occurred in 46 (77%) and 29 (48%) patients, respectively. Median PFS was 251d (95% CI 147-337). At week 9, median tumour microenvironment androgens, precursors, and nuclear AR expression decreased (p<0.001). The baseline tumour AR C/N terminal ratio of ?80% was associated with treatment benefit. At enzalutamide steady state, abiraterone acetate Cmin was ?23% lower (range 14.05-200.5ng/ml) than when given alone. CONCLUSIONS:Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC. PATIENT SUMMARY:This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.

Project description:ImportanceOlder adults are at greater risk of cognitive decline with various oncologic therapies. Some commonly used therapies for advanced prostate cancer, such as enzalutamide, have been linked to cognitive impairment, but published data are scarce, come from single-group studies, or focus on self-reported cognition.ObjectiveTo longitudinally examine the association between cognitive function and docetaxel (chemotherapy), abiraterone, enzalutamide, and radium Ra 223 dichloride (radium 223) in older men with metastatic castration-resistant prostate cancer.Design, setting, and participantsA multicenter, prospective, observational cohort study was conducted across 4 academic cancer centers in Ontario, Canada. A consecutive sample of 155 men age 65 years or older with metastatic castration-resistant prostate cancer starting any treatment with docetaxel, abiraterone acetate, enzalutamide, or radium Ra 223 dichloride (radium 223) were enrolled between July 1, 2015, and December 31, 2019.ExposuresFirst-line chemotherapy (docetaxel), abiraterone, enzalutamide, or radium 223.Main outcomes and measuresCognitive function was measured at baseline and end of treatment using the Montreal Cognitive Assessment, the Trail Making Test part A, and the Trail Making Test part B to assess global cognition, attention, and executive function, respectively. Absolute changes in scores over time were analyzed using univariate and multivariable linear regression, and the percentages of individuals with a decline of 1.5 SDs in each domain were calculated.ResultsA total of 155 men starting treatment with docetaxel (n = 51) (mean [SD] age, 73.5 [6.2] years; 34 [66.7%] with some postsecondary education), abiraterone (n = 29) (mean [SD] age, 76.2 [7.2] years; 18 [62.1%] with some postsecondary education), enzalutamide (n = 54) (mean [SD] age, 75.7 [7.4] years; 33 [61.1%] with some postsecondary education), and radium 223 (n = 21) (mean [SD] age, 76.4 [7.2] years; 17 [81.0%] with some postsecondary education) were included. Most patients had stable cognition or slight improvements during treatment. A cognitive decline of 1.5 SDs or more was observed in 0% to 6.5% of patients on each measure of cognitive function (eg, 3 of 46 patients [6.5%; 95% CI, 2.2%-17.5%] in the group receiving chemotherapy [docetaxel] had a decline of 1.5 SDs for Trails A and Trails B). Although patients taking enzalutamide had numerically larger declines than those taking abiraterone, differences were small and clinically unimportant.Conclusions and relevanceThese findings suggest that most older men do not experience significant cognitive decline in attention, executive function, and global cognition while undergoing treatment for advanced prostate cancer regardless of the treatment used.

Project description:BackgroundAbiraterone acetate plus prednisolone is approved to treat patients with castration-resistant prostate cancer. This study evaluated the safety and efficacy of abiraterone acetate plus prednisolone in castration-resistant prostate cancer patients with or without previous chemotherapy in a real-world setting in Japan.MethodsThis study was an observational, prospective, post-marketing surveillance. Castration-resistant prostate cancer patients, who initiated abiraterone acetate after its approval in Japan, were enrolled. Data were collected during an observation period of 12 months and a follow-up period of another 12 months. Adverse events and adverse drug reactions were evaluated for safety. Prostate-specific antigen levels and overall survival were evaluated for efficacy.ResultsFrom 141 participating institutions, 497 patients were registered: 492 patients including 180 chemotherapy-naïve, 311 chemotherapy-experienced and one off-label-use patient received abiraterone and were evaluated for safety. Adverse events were observed in 225/492 patients (45.7%), adverse drug reactions in 131/492 patients (26.6%) and serious adverse drug reactions in 61/492 patients (12.4%). The most commonly observed adverse drug reaction was abnormal hepatic function (6.5%), followed by hypokalemia (3.0%) and decreased appetite (2.0%). At week 12, 110/432 patients (25.5%) achieved ≥50% decrease from baseline in prostate-specific antigen, and the proportion was higher in chemotherapy-naïve patients (56/161 patients; 34.8%) compared with chemotherapy-experienced patients (54/271 patients; 19.9%, P < 0.001). Survival rates at 24 months were 68.3% (295/432 patients), 73.9% (119/161 chemotherapy-naïve patients) and 64.9% (176/271 chemotherapy-experienced patients).ConclusionsThis large-scale, real-world, post-marketing surveillance study confirmed the safety and efficacy of abiraterone acetate plus prednisolone in Japanese castration-resistant prostate cancer patients with or without previous chemotherapy.