Use Of Enzalutamide Research Articles

Analysis of innovative clinical developments in the field of therapy for metastatic prostate cancer: bright results of the ASCO Congress-2022

Introduction. Prostate cancer (PC), according to the results for 2019, is the second most frequently diagnosed malignant tumor in men living in the Russian Federation. There is a significant proportion of patients with advanced (III-IV stages) of prostate cancer - up to 50 %, while metastatic cancer accounts for up to 18.1 % of patients. Popularization in the Moscow City Healthcare clinical practice of innovative technologies for managing patients with metastatic castration-resistant prostate cancer (mCRPC) directly meets the goals and objectives of the Federal project aimed at increasing the life expectancy of cancer patients.
 Materials and methods. The article reviews the results of clinical developments in the field of mCRPC treatment presented at The ASCO Annual Meeting, June 3-7, 2022: VISION sub-studies, TheraP study, study of the prognostic role of circulating tumor DNA (ctDNA) in the early choice of a strategy for the use of abiraterone or enzalutamide in patients with initial mCRPC - treatment naïve - status.
 Results and discussion. The volume of clinical information on the results of theranostic antitumor radiation technologies implemented with the participation of prostate-specific membrane antigen (hereinafter referred to as PSMA) is growing rapidly. PSMA - mediated radio-imaging is considered as a potentially effective tool for selecting patients who are sensitive to specific therapy. When studying radionuclide therapy mediated by a ligand to PSMA (PSMA-L), the main efforts are focused on determining the optimal regimens for its clinical application. The possibility of expanding the current indications for prescribing 177Lu-PSMA-617 to patients with prostate cancer at an earlier stage is also being studied. Until final results are obtained from clinical trials that provide clear answers to open questions regarding various aspects of the application of innovative PSMA - mediated theranostic technologies, it remains very important to reach an expert consensus, within the framework of an exchange of opinions, re arding their appropriate use in various clinical situations.

Immediate Prostate-specific Antigen Decline After Enzalutamide Following Abiraterone Predicts Survival in Castration-resistant Disease.

Although the sequential use of abiraterone and enzalutamide is not recommended because of possible cross-resistance, many patients with metastatic castration-resistant prostate cancer (mCRPC) are receiving sequential abiraterone and enzalutamide in the real world, and a subset of patients can benefit from sequential therapy with these drugs. This study aimed to identify patients who could benefit from the sequential use of enzalutamide after abiraterone use. We included 70 patients with mCRPC who received enzalutamide sequentially following abiraterone treatment. Decline in the prostatespecific antigen (PSA) levels at 4 weeks after enzalutamide initiation and the association between decline in PSA levels and survival were analyzed. Sixteen men (22.9%) achieved a decline of >50% in PSA levels after 4 weeks of enzalutamide administration. Overall survival (OS) after enzalutamide among men with >50% decline at 4 weeks was significantly better than that among men with a PSA decline <50% (not reached vs. 34 months, p=0.008). OS after first-line abiraterone treatment for men with PSA decline >50% and <50% was not reached and 46 months, respectively (p=0.007). A PSA decline of >50% at 4 weeks of enzalutamide administration was an independent predictor of longer OS. A PSA decline of >50% at 4 weeks after the start of sequential enzalutamide treatment following abiraterone treatment predicted long-term survival in patients with mCRPC. Early PSA decline can identify patients who benefit from second-line enzalutamide after abiraterone treatment and can be useful as a decision-making tool regarding treatment.

Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment.

Enzalutamide is a nonsteroidal inhibitor of the androgen receptor (AR) signaling pathway and is used to treat patients with metastatic castration-resistant prostate cancer. However, the risk of cardiovascular-related hospitalization in patients with no contraindications for the use of enzalutamide is about 1–2%. To date, the underlying molecular basis of this has not been established. The androgen receptor, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are nuclear receptors that share structural similarities and have closely related DNA-binding sites and coregulators. In non-epithelial cells, a fine balance of the activities of these receptors is essential to ensure correct cellular function. In this study, we present a molecular characterization of these nuclear receptors in a prostate cancer patient who developed congestive heart failure after enzalutamide treatment. White cell RNAseq revealed a homozygous rs5522 MR polymorphism and both the rs143711342 and rs56149945 GR polymorphisms, carried in different alleles. No different specific splice isoforms were detected. Recent research suggests that AR inhibition by enzalutamide makes available a coregulator that specifically interacts with the rs5522-mutated MR, increasing its activity and producing adverse effects on cardiovascular health. We suggest an evaluation of the MR rs5522 polymorphism before starting therapy with AR inhibitors.

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

BackgroundEnzalutamide (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. ObjectiveTo evaluate whether ENZ or ABI is better as first-line treatment for CRPC. Design, setting, and participantsAn 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 analysisThe 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 limitationsAfter 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). ConclusionsENZ 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 summaryResults from our study suggest that use of enzalutamide before abiraterone may have potential clinical benefits for patients with castration-resistant prostate cancer.

Pharmacoeconomic evaluation of using enzalutamide for treatment of patients with metastatic hormone-sensitive prostate cancer

Background. The addition of enzalutamide to standard androgen deprivation therapy (ADT) significantly increases overall survival and progression-free survival in patients with metastatic hormone-sensitive prostate cancer (mHSPC) compared with ADT.Objective: to evaluate the incremental cost/effectiveness ratio (ICER) of enzalutamide use in patients with mHSPC and the ICER of enzalutamide as the first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) from the Russian healthcare system perspective and to assess the contribution of enzalutamide into the reduction of mortality of mHSPC patients in the Russian Federation on the horizon until 2024.Materials and methods. Standard ADT regimens for mHSPC were used as a comparator as it is the most common treatment for mHSPC in Russia. We proposed a Markov model of mHSPC progression on enzalutamide + ADT (hereinafter enzalutamide) or ADT + 1st generation antiandrogen (hereinafter ADT) based on ENZAMET trial data. Model was used to calculate the average life-years gained (LYG) and costs of mHSPC and post-progression mCRPC treatment. Simulation period was 15 years with one cycle of 1 month. In the “cost–effectiveness” analysis, we calculated enzalutamide ICER compared to ADT. In addition, we calculated ICER for enzalutamide plus ADT vs ADT in the first-line therapy of mCRPC as a benchmark based on PREVAIL trial data. In both cases, the average LYG over a 15-year period was used as an efficacy criteria. To assess the contribution of the enzalutamide into the reduction of mortality rate of mHSPC patients, the potential number of patients who could be treated with enzalutamide on the horizon of 2021–2024 was taken into account.Results. According to the Markov model, the average LYG over a period of 15 years for enzalutamide was 7.59 years compared to 5.12 for ADT. The average enzalutamide therapy costs were 11,193,802 rubles per patient for 15 years, which were 8,597,131 rubles higher than when using ADT (2,596,672 rubles). ICER for enzalutamide (vs ADT) in mHSPC treatment was 3,484,362 rubles per one life-year gained. ICER for enzalutamide in the first line of mCRPC treatment (vs ADT) was 5,899,418 rubles per one life-year gained. The combination therapy with enzalutamide + ADT in Russia can be started annually by 2,410 mHSPC patients. If they all receive enzalutamide a total of 561 averted deaths among prostate cancer patients can be expected in 2021–2024.Conclusion. In the Russian healthcare system, ICER for enzalutamide in mHSPC was 3,484,362 rubles and the ICER for enzalutamide in mCRPC was 5,899,418 rubles. Enzalutamide can make a significant contribution to achieving the target cancer mortality rates by 2024.

MP48-19 RISK OF METABOLIC AND CARDIOVASCULAR ADVERSE EVENTS WITH ABIRATERONE OR ENZALUTAMIDE AMONG MEN WITH ADVANCED PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022MP48-19 RISK OF METABOLIC AND CARDIOVASCULAR ADVERSE EVENTS WITH ABIRATERONE OR ENZALUTAMIDE AMONG MEN WITH ADVANCED PROSTATE CANCER Lillian Lai, Mary Oerline, Megan Caram, Phoebe Tsao, Samuel Kaufman, Brent Hollenbeck, and Vahakn Shahinian Lillian LaiLillian Lai More articles by this author , Mary OerlineMary Oerline More articles by this author , Megan CaramMegan Caram More articles by this author , Phoebe TsaoPhoebe Tsao More articles by this author , Samuel KaufmanSamuel Kaufman More articles by this author , Brent HollenbeckBrent Hollenbeck More articles by this author , and Vahakn ShahinianVahakn Shahinian More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002619.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Abiraterone and enzalutamide, used with androgen deprivation, are the most common treatments for men with advanced prostate cancer. Both have anti-androgenic properties and abiraterone is prescribed with prednisone, which may contribute to metabolic or cardiovascular adverse events. To understand the safety of abiraterone and enzalutamide use in real-world settings, we examined the association between the use of these agents and the risk of metabolic or cardiovascular events while on treatment. METHODS: 56,230 men with advanced prostate cancer were identified in a 20% sample of the 2011-2017 national Medicare claims. Abiraterone or enzalutamide use was analyzed as a time-dependent covariate. The primary outcome was the occurrence of a major metabolic or cardiovascular event, defined as an emergency room visit or hospitalization associated with a primary diagnosis of diabetes, hypertension, or cardiovascular disease. The secondary outcome was the occurrence of a minor metabolic or cardiovascular event, defined as an outpatient visit associated with a primary diagnosis of the aforementioned conditions. Men who experienced an event of interest in the 12 months prior to the study start date were excluded. The risks of primary and secondary composite outcomes were assessed using Cox regression. The occurrence of adverse events by specific diagnoses was also examined individually. RESULTS: Per unadjusted incidence rates, men receiving abiraterone had 1 additional emergency room visit/hospitalization due to a cardiovascular event for every 29 men treated (median time on drug: 4.7 months). Compared to men not receiving abiraterone, men receiving the drug were at increased risk of both a major composite adverse event (HR 1.77 95% CI 1.53-2.05 p <0.01) and a minor composite adverse event (HR 1.24 95% CI 1.05-1.47 p=0.01) (Table). Compared to men not receiving enzalutamide, men receiving enzalutamide were at an increased risk of a major composite adverse event (HR 1.22 95% CI 1.01-1.48 p=0.04) but not a minor composite adverse event (HR 1.04 95% CI 0.83-1.30 p=0.75). CONCLUSIONS: Treatment with abiraterone or enzalutamide is associated with increased risk of major metabolic or cardiovascular events in real-world settings. Source of Funding: AHRQ R01HS027507NCI T32 CA180984 Prostate Cancer Foundation © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e828 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lillian Lai More articles by this author Mary Oerline More articles by this author Megan Caram More articles by this author Phoebe Tsao More articles by this author Samuel Kaufman More articles by this author Brent Hollenbeck More articles by this author Vahakn Shahinian More articles by this author Expand All Advertisement PDF DownloadLoading ...

Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In primary analysis, enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC); however, overall survival data were immature. In the phase III, double-blind, global ARCHES trial (ClinicalTrials.gov identifier: NCT02677896), 1,150 patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. Here, we report the final prespecified analysis of overall survival (key secondary end point) and an update on rPFS, other secondary end points, and safety. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of May 28, 2021 (median follow-up, 44.6 months), 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died. Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT (median not reached in either group; hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P < .001). Enzalutamide plus ADT continued to improve rPFS and other secondary end points. Adverse events were generally consistent with previous reports of long-term enzalutamide use. In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC.

Risk of Metabolic and Cardiovascular Adverse Events With Abiraterone or Enzalutamide Among Men With Advanced Prostate Cancer.

Abiraterone and enzalutamide are the most common oral agents for the treatment of men with advanced prostate cancer. To understand their safety profiles in real-world settings, we examined the association between the use of abiraterone or enzalutamide and the risk of metabolic or cardiovascular adverse events while on treatment. Men with advanced prostate cancer and their use of abiraterone or enzalutamide were identified in a 20% sample of the 2010-2017 national Medicare claims. The primary composite outcome was the occurrence of a major metabolic or cardiovascular adverse event, defined as an emergency room visit or hospitalization associated with a primary diagnosis of diabetes, hypertension, or cardiovascular disease. The secondary composite outcome was the occurrence of a minor metabolic or cardiovascular adverse event, defined as an outpatient visit associated with a primary diagnosis of the aforementioned conditions. Risks were assessed separately for abiraterone and enzalutamide using Cox regression. All statistical tests were 2-sided. Compared with men not receiving abiraterone, men receiving abiraterone were at increased risk of both a major composite adverse event (hazard ratio [HR] = 1.77, 95% confidence interval [CI] = 1.53 to 2.05; P < .001) and a minor composite adverse event (HR = 1.24, 95% CI = 1.05 to 1.47; P = .01). Compared with men not receiving enzalutamide, men receiving enzalutamide were at an increased risk of a major composite adverse event (HR = 1.22, 95% CI = 1.01 to 1.48; P = .04) but not a minor composite adverse event (HR = 1.04, 95% CI = 0.83 to 1.30; P = .75). Careful monitoring and management of men on abiraterone or enzalutamide through team-based approaches are critical.

Physician Dispensing Among Urology Practices and the Use of Abiraterone or Enzalutamide for Men With Advanced Prostate Cancer.

Urologists are increasingly prescribing oral targeted therapies to patients with advanced prostate cancer. Concurrent with this trend, urology practices are allowing patients to fill their prescription onsite or through a pharmacy established by the practice. We examined prescription patterns for abiraterone or enzalutamide between eventually dispensing single-specialty urology practices, nondispensing single-specialty urology practices, and multispecialty practices using a 20% random sample of the 2013-2017 national Medicare claims. We determined physician dispensing through manual search of publicly available information. From 2015 through 2017, higher percentages of patients managed by eventually dispensing single-specialty urology practices had a filled prescription of abiraterone or enzalutamide compared with patients managed in nondispensing single-specialty urology practices (eg, in 2017, 8.9%, 95% confidence interval = 7.3% to 10.9%, vs 5.9%, 95% confidence interval = 5.0% to 7.0%, respectively; 2-sided P < .001). Insofar as physician dispensing is associated with higher use of abiraterone or enzalutamide, it may represent a means to improve treatment access.

Enzalutamide versus abiraterone plus prednisolone before chemotherapy for Japanese castration-resistant prostate cancer patients: An investigator-initiated, multicenter, randomized controlled trial.

122 Background: Enzalutamide and abiraterone plus prednisolone demonstrated improvement of survival for castration-resistant prostate cancer (CRPC). However, it remains quite unclear which agent is better in terms of efficacy and safety for Asian patients. Methods: An investigator-initiated, multicenter, randomized controlled trial was conducted in Japan. CRPC patients before chemotherapy were randomly assigned to the enzalutamide or the abiraterone plus prednisolone arm (1:1). The primary endpoint is time to prostate-specific antigen (PSA) progression and secondary endpoints include PSA response rate (≥50% decline from baseline), overall survival, radiographic progression-free survival, and safety assessment. Results: Between February 20, 2015 and July 30, 2019, 203 patients were enrolled. After randomization, 92 in the enzalutamide and 92 in the abiraterone plus prednisolone arm were treated and analyzed. Time to PSA progression was not significantly different between arms (median 21.2 and 11.9 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.81, 95% CI 0.51-1.27, p = 0.1732). There was a significant difference in PSA response rate between arms (72% and 57% in the enzalutamide and the abiraterone plus prednisolone arm, respectively, p = 0.0425). There were no significant differences in overall and radiographic progression-free survival between arms (median 32.9 and 35.5months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 1.17, 95% CI 0.72-1.88, p = 0.5290 and median 17.6 and 14.0 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.92, 95% CI 0.63-1.34, p = 0.6532). Grade ≥3 of adverse events were observed in 11% and 21% in the enzalutamide and the abiraterone plus prednisolone arm, respectively ( p = 0.1044). Conclusions: Enzalutamide did not show any survival benefits compared with abiraterone plus prednisolone but showed better PSA response rate with no significant differences of severe adverse event rate for Japanese CRPC patients. Our data suggest that antecedent use of enzalutamide to abiraterone plus prednisolone have potentially clinical benefits in Asian CRPC populations. Clinical trial information: UMIN000015529.

Impact of the COVID-19 pandemic on the diagnosis and treatment of men with prostate cancer.

To determine the impact of the COVID-19 pandemic on diagnostic and treatment activity in 2020 across hospital providers of prostate cancer (PCa) care in the English National Health Service. Diagnostic and treatment activity between 23 March (start of first national lockdown in England) and 31 December 2020 was compared with the same calendar period in 2019. Patients newly diagnosed with PCa were identified from national rapid cancer registration data linked to other electronic healthcare datasets. There was a 30.8% reduction (22 419 vs 32 409) in the number of men with newly diagnosed PCa in 2020 after the start of the first lockdown, compared with the corresponding period in 2019. Men diagnosed in 2020 were typically at a more advanced stage (Stage IV: 21.2% vs 17.4%) and slightly older (57.9% vs 55.9% ≥ 70 years; P < 0.001). Prostate biopsies in 2020 were more often performed using transperineal (TP) routes (64.0% vs 38.2%). The number of radical prostatectomies in 2020 was reduced by 26.9% (3896 vs 5331) and the number treated by external beam radiotherapy (EBRT) by 14.1% (9719 vs 11 309). Other changes included an increased use of EBRT with hypofractionation and reduced use of docetaxel chemotherapy in men with hormone-sensitive metastatic PCa (413 vs 1519) with related increase in the use of enzalutamide. We found substantial deficits in the number of diagnostic and treatment procedures for men with newly diagnosed PCa after the start of the first lockdown in 2020. The number of men diagnosed with PCa decreased by about one-third and those diagnosed had more advanced disease. Treatment patterns shifted towards those that limit the risk of COVID-19 exposure including increased use of TP biopsy, hypofractionated radiation, and enzalutamide. Urgent concerted action is required to address the COVID-19-related deficits in PCa services to mitigate their impact on long-term outcomes.

Sequencing of Systemic Therapies in the Management of Advanced Prostate Cancer in India: a Delphi-Based Consensus.

IntroductionWith the availability of an increasing number of therapeutic options for advanced prostate cancer (APC), optimal sequencing and combination of therapies have emerged to be the areas of challenges. In the Indian context, there is a dearth of consensus recommendations to guide clinicians regarding optimal sequencing of therapy in APC management. A Delphi-based consensus regarding optimal therapy sequencing in APC management was developed by an expert panel of medical oncologists from across India. MethodsAn expert scientific committee of 11 medical oncologists and an expert panel of 53 medical oncologists from India constituted the panel for the Delphi consensus. In the first phase, a questionnaire with 41 clinical statements was developed in several critical controversial areas in APC treatment. In the second phase, 29 clinical statements were reworked and sent to eight experts to obtain their opinions on best practices. The consensus ratings were based on a 9-point Likert scale. Based on the overall response, statements with a mean score of ≥ 7 with 1 outlier were considered as “consensus.”ResultsDegarelix was the preferred androgen deprivation therapy (ADT). While ADT plus docetaxel was the preferred option for metastatic castrate-sensitive/naïve prostate cancer patients with high-volume disease, ADT with abiraterone was the preferred choice for low-volume disease. Docetaxel was the preferred first-line treatment option in men who received ADT alone in the castrate-sensitive/naïve setting. For patients progressing on or after docetaxel for metastatic castrate-resistant prostate cancer (without prior abiraterone or enzalutamide), the experts reached a consensus on the use of enzalutamide as the preferred second-line treatment option. No consensus was reached for the third-line treatment options.ConclusionThis article is intended to serve as a guide to help clinicians discuss with their patients as part of the shared and multidisciplinary decision-making for improved APC management in India.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40487-021-00181-1.

Real-world use of enzalutamide in men with nonmetastatic castration-resistant prostate cancer in Japan

BackgroundThe purpose of the study is to evaluate real-world effectiveness and safety of enzalutamide in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) in Japan.MethodsThis was a retrospective evaluation of medical records from men in Japan who started enzalutamide treatment from November 1, 2014, to March 31, 2018, and received androgen deprivation therapy throughout. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included PSA response rate, time to first use of new antineoplastic therapy, time to first use of cytotoxic chemotherapy, and enzalutamide treatment duration. An exploratory analysis of metastasis-free survival (MFS) was also performed. Adverse events (AEs) were analyzed to assess safety.ResultsBased on data from medical records of 205 men in Japan, median time to PSA progression was 27 months (95% confidence interval [CI] 19–not reached [NR]), with 82.5% and 52.0% of men achieving PSA response rates of ≥ 50% and ≥ 90%, respectively. Median time to first use of new antineoplastic therapy was 36 months (95% CI 27−NR) and median enzalutamide treatment duration was 13 months (interquartile range: 7–24). Median time to first use of cytotoxic chemotherapy was NR (95% CI 41−NR). Median MFS was 29 months (95% CI 23−35). In total, 51.7% of men experienced AEs, with malaise (18.5%), decreased appetite (10.7%), and nausea (4.9%) the most frequently reported.ConclusionsThis is the first study to demonstrate the real-world effectiveness and safety of enzalutamide in men with nmCRPC in Japan, further informing healthcare providers about available treatment options for this patient population.

Patient Preference Between Cabazitaxel and Docetaxel for First-line Chemotherapy in Metastatic Castration-resistant Prostate Cancer: The CABADOC Trial

BackgroundThe taxanes docetaxel and cabazitaxel prolong overall survival for men with metastatic castration-resistant prostate cancer (mCRPC), with cabazitaxel approved in the postdocetaxel setting only. Recent data suggest they have similar efficacy but a different safety profile in the first-line mCRPC setting. ObjectiveTo assess patient preference between docetaxel and cabazitaxel among men who received one or more doses of each taxane and did not experience progression after the first taxane. Design, setting, and participantsChemotherapy-naïve patients with mCRPC were randomized 1:1 to receive docetaxel (75 mg/m2 every 3 wk × 4 cycles) followed by cabazitaxel (25 mg/m2 every 3 wk × 4 cycles) or the reverse sequence. Randomization was stratified by prior abiraterone or enzalutamide use. Outcome measurements and statistical analysisThe primary endpoint was patient preference, assessed via a dedicated questionnaire after the second taxane. Secondary endpoints included reasons for patient preference, prostate-specific antigen response, radiological progression-free survival, and overall survival. This clinical trial is registered at ClinicalTrials.gov as NCT02044354. Results and limitationsOf 195 men randomized, 152 met the prespecified modified intent-to-treat criteria for analysis. Overall, 66 patients (43%) preferred cabazitaxel, 40 (27%) preferred docetaxel, and 46 (30%) had no preference (p = 0.004, adjusted for treatment period effect). More patients preferred treatment period 1 (43%, 95% confidence interval [CI] 36–52%) versus period 2 (27%, 95% CI 20–34%). Patient preference for cabazitaxel was mainly related to less fatigue (72%), better quality of life (64%), and other adverse events (hair loss, pain, nail disorders, edema). Adverse events were consistent with the known safety profile of each drug. ConclusionsA significantly higher proportion of chemotherapy-naïve men with mCRPC who received both taxanes preferred cabazitaxel over docetaxel. Less fatigue and better quality of life were the two main reasons driving patient choice. Patient summaryMen with metastatic castration-resistant prostate cancer preferred cabazitaxel over docetaxel for chemotherapy, mainly because of less fatigue and better quality of life.

Risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients

BackgroundAbiraterone and enzalutamide use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude and clinical relevance of this association in real-world prostate cancer (PC) population remain unknown.Materials and methodsWe retrospectively reviewed the MarketScan claims databases (1 January 2013 to 30 September 2018) to identify adults with diagnosis of metastatic PC who received treatment with androgen deprivation therapy (ADT) and novel antiandrogen agents (abiraterone or enzalutamide). The primary CV outcome measure was composite outcome of acute myocardial infarction (MI) or stroke. Secondary outcomes were individual risks of MI or stroke. We used an intention-to-treat approach to analyze the CV outcomes associated with drug exposure among patients with metastatic PC. Cox regression model was used to estimate the independent association of two drugs with CV risk after adjustment for age, baseline atrial fibrillation, and Charlson Comorbidity Index.ResultsA total of 6294 patients with metastatic PC who were treated with ADT and either abiraterone or enzalutamide were included in the final analysis. Of these, 4017 (63.8%) patients used abiraterone and 2217 (32.2%) patients used enzalutamide. During the study period, 255 (6.3%) primary endpoint events occurred, resulting in an incidence rate of 4.3 per 100 patient-years. In multivariable analysis, abiraterone use was associated with a 31% increased risk of MI or stroke compared to enzalutamide (hazard ratio 1.31; 95% confidence interval 1.05-1.63; P = 0.01). The incidence rate was similar in patients who switched initial therapy from abiraterone to enzalutamide or vice versa (5.0 versus 5.6 per 100 patient-years, respectively).ConclusionsTo our knowledge, this is the first real-world assessment of MI and stroke among metastatic PC patients receiving novel anti-androgens. Our findings of increased MI and stroke risk with abiraterone compared with enzalutamide are consistent with data from clinical trials and suggest that enzalutamide may be preferable for prostate cancer patients at high CV risk.

High Tumor Burden Predicts Poor Response to Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients

Simple SummarySeveral available medications are involved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). In this Taiwanese mCRPC cohort receiving enzalutamide patients with high tumor burden (HTB) were defined as those with either appendicular bony metastasis or visceral metastasis. A high tumor burden reduced the PSA response rate, radiological response rate, and progression-free survival duration. In addition, patients’ comorbidities and laboratory data—such as ALP, LDH, ALT, and hemoglobin—were correlated with the treatment efficacy of enzalutamide. Our study revealed a tumor burden before the use of enzalutamide was associated with treatment outcomes. The physician can use this information to estimate the response rate of enzalutamide and help formulate a personalized treatment plan for mCRPC patients.To assess the predictive value of tumor burden on the biochemical response, and radiological response in Taiwanese metastatic castration-resistant prostate cancer (mCRPC) patients receiving enzalutamide. The mCRPC patients treated with enzalutamide were recruited from three hospitals. High tumor burden (HTB) was classified as metastases at either appendicular bone or visceral organ. Good prostate-specific antigen (PSA) response was defined as PSA reduction of 80%. In this cohort, there were 104 (54.2%) HTB patients and 88 (45.8%) with low tumor burden (LTB). Compared to LTB patients, fewer HTB patients had good PSA response (odds ratio: 0.43, range: 0.22–0.87, p = 0.019) and fewer radiological response (complete and partial remission) (odds ratio: 0.78, range: 0.36–1.68, p = 0.52) to enzalutamide. The disease control rate which also contained stable disease, was still lower in HTB (76.0%) than LTB group (92.9%, OR: 0.24, range: 0.07–0.77, p = 0.016) in the multivariable model. In addition, HTB patients had significantly shorter progression–free survival duration than did LTB patients (median: 8.3 vs. 21.6 months, log-rank test p = 0.003) in the univariable analysis. The tumor burden before the use of enzalutamide was associated with treatment outcomes. HTB reduced PSA response rate, radiological response rate and progression-free survival duration.

Abstract 2070: Androgen deprivation and its impact on DNA repair in combination with ionising radiation and Radium-223 in prostate cancer

Abstract Abiraterone acetate and Enzalutamide are novel anti-androgens shown to be one of the few treatments to improve both progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. However, many questions exist regarding the optimal combination and scheduling with radiation, the degree of additivity or synergism and the underlying mechanisms governing any potential synergy. This study is attesting the biological rationale for the selection of Abiraterone or Enzalutamide as, currently, the choice of therapy is a clinical decision based on experience and side effect profiles. As well as external beam radiotherapy a key unexplored area of interest is the combination of these inhibitors with the α-emitter radium-223, which targets bone metastases, with preliminary studies, such as the ERA-223 study, highlighting the need for further studies to mechanistically determine if these combinations are effective and safe. To better understand this, we conducted a detailed analysis of the effects of Abiraterone (10µM), Enzalutamide (10µM) or DMSO (Control) alone or in combination with a dose range of X-rays and radium-223 exposure on cell cycle, DNA damage, DNA repair and cell viability across a panel of androgen-insensitive (PC3), androgen-sensitive (LNCaP) and osteoblastic bone models (SJSA-1, SAOS-2). We report significant differences in the synergy of these AR inhibitors in combination with radiation, with Abiraterone causing significant radiosensitisation regardless of AR status and radiosensitisation with Enzalutamide being dependent on AR-sensitivity. This suggests a potential alternative mechanism of action of Abiraterone, not dependent on AR status. AR suppression alone was also shown to impact cell-cycle distribution, with most notable changes being increases in sub-G1 at the expense of S phase, with observed increases in PARP-cleavage supporting this being a result of increased levels of apoptosis and potential reductions in RAD51 levels. Studies with radium-223 confirmed the highly damaging nature of α-particles, with radium-223 treatments shown to be highly cytotoxic compared to equivalent doses of X-rays. Compared to X-rays, radium-223 induced cell cycle distribution changes in the form of much larger shifts towards G2, which also took longer to recover. As well as increased levels of apoptosis through observed increases in PARP-cleavage. Combinations of radium-223 with Abiraterone or Enzalutamide led to a loss of all additive or synergistic effects previously measured with X-rays. Most likely due to the highly cytotoxic nature of α-particles due to the induction of non-reparable DNA dsb. In conclusion, these results support the use of Abiraterone and Enzalutamide in combination with X-rays and radium-223 to enhance tumor response independently of androgen receptor status. Citation Format: Timothy Wright, Victoria Dunne, Aidan Cole, Kevin Prise. Androgen deprivation and its impact on DNA repair in combination with ionising radiation and Radium-223 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2070.

Mental health care utilization among veterans with castration-resistant prostate cancer receiving abiraterone or enzalutamide.

e18680 Background: Abiraterone and enzalutamide are oral therapies widely used to treat men with castration-resistant prostate cancer (CRPC). Recent data have suggested potentially worsened quality of life and depression with use of enzalutamide compared to abiraterone. Because Veterans are at a higher risk for mental health conditions, we sought to compare mental health service utilization in Veterans with CRPC receiving enzalutamide to those receiving abiraterone. Methods: The Veterans Health Administration Corporate Data Warehouse was used to identify men with CRPC who received abiraterone or enzalutamide for ≥ 30 days as first-line treatment between 2010-2017. We compared the rate of mental health visits per 100 patient-months for men on abiraterone versus enzalutamide using an exact rate ratio test, assuming Poisson counts. Results: Among 2902 male Veterans, 68.6% (n=1992) received abiraterone and 31.4% (n=910) enzalutamide as first-line therapy. Men who received enzalutamide were older (76 vs 74, p&lt;0.01) and had a higher comorbidity burden (Charlson Comorbidity Index [CCI] ≥ 2 in 28.7% vs 21.6%, p&lt;0.01); no differences were noted in race or prevalence of preexisting documented mental health diagnoses. Median time on drug was 8 months for both medications. There was no difference in the rate of mental health visits per 100 patients-months on enzalutamide versus abiraterone (6.6 v. 6.7, p=0.66). However, within patient sub-groups, men who were age 75 or older, not married, or without notable comorbidities had lower rates of mental health visits with enzalutamide compared to abiraterone; whereas those who were younger than 75, married, had higher comorbidities, or a preexisting mental health diagnosis had higher rates of mental health visits with enzalutamide (Table). Conclusions: Among Veterans with CRPC who received a novel antiandrogen therapy first-line, there was no difference in engagement in mental health care between those who received abiraterone versus enzalutamide. Sub-group analysis revealed significant differences between patients on the two medications in demographic and diagnostic characteristics associated with number of visits, suggesting that vulnerability for mental health symptoms may vary by medication type. Further work in understanding the long-term impact of novel antiandrogens on mental health is needed.[Table: see text]

Consensus on the Treatment and Follow-Up for the Nonmetastatic Castration-Resistant Prostate Cancer: A Report From the First Prostate Cancer Consensus Conference for Developing Countries

PURPOSETo present a summary of the recommendations for the treatment and follow-up for the biochemical recurrence of castration-resistant prostate cancer (PCa) as acquired through a questionnaire administered at the Prostate Cancer Consensus Conference for Developing Countries.METHODSA total of 27 questions were identified as relating to this topic. Responses from the clinician were tallied and are presented in percentage format. Topics included the use of imaging in staging, treatment recommendations across different patient scenarios of life expectancy and prostate-specific antigen (PSA) doubling time, and follow-up for nonmetastatic castration-resistant PCa.RESULTSA consensus agreed that in optimal conditions, positron emission tomography-computed tomography with prostate-specific membrane antigen would be used although in limited resource situations the combined use of CT of the abdomen and pelvic (or pelvic MRI), a bone scan, and a CT of the thorax or chest x-ray was recommended. In cases when PSA levels double in < 10 months, more than 90% of clinicians agreed on the use of apalutamide or enzalutamide, regardless of life expectancy. With a doubling time of more than 10 months, > 54% of experts recommended no treatment independent of life expectancy. More than half of the experts, regardless of resources, recommended follow-up with a physical examination and PSA levels every 3-6 months and imaging only in the case of symptoms.CONCLUSIONThe voting results and recommendations presented in this document can be used by physicians to support management for biochemical recurrence of castration-resistant PCa in areas of limited resources. Individual clinical decision making should be supported by available data.

Impact of concomitant prostate cancer therapy on efficacy and safety of relugolix versus leuprolide in men with advanced prostate cancer: Subgroup analysis from the phase III HERO study.

106 Background: In the phase 3 HERO study, the oral GnRH receptor antagonist, relugolix, demonstrated suppression of testosterone to castrate levels in 96.7% of patients, which was superior to leuprolide, and a 54% lower risk of major adverse cardiovascular events relative to leuprolide. To characterize the impact of concomitant prostate cancer treatments with the use of relugolix in advanced prostate cancer from the HERO study, a subgroup analysis for patients receiving various therapies was undertaken. Methods: The HERO study was designed to evaluate relugolix in men with advanced prostate cancer. Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide (ENZ) or docetaxel (DOC) 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (&lt;50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant ENZ, DOC, and any radiation therapy (RT). A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Results: Overall, 125 patients (13.4%) took at least one concomitant therapy that could impact testosterone levels. RT was received by 15.9% and 18.8% of patients in the relugolix and leuprolide groups, respectively. ENZ was the most frequently used therapy in the relugolix group (2.7%), with similar use in the leuprolide group (1.9%). DOC was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in &lt;1% of population. The sensitivity analysis results indicated that use of these concomitant therapy that could affect testosterone levels did not impact the primary endpoint. Castration rates were similar with and without concomitant use of ENZ and DOC, or RT (table). No clinically relevant differences in adverse events were observed between patients with or without concomitant use of ENZ, DOC, or RT in either treatment group. Conclusions: While the numbers are small, treatment with relugolix was associated with a similar efficacy and safety profiles in patients who received concomitant administration of ENZ, DOC, or RT to that observed in patients not receiving those concomitant treatments. Clinical trial information: NCT03085095. [Table: see text]