Enzalutamide In Patients Research Articles

Study of I-131-1095 Radiotherapy in Combination With Enzalutamide in Patients With Metastatic Castration-resistant Prostate Cancer Who Are Chemotherapy Naive and Have Progressed on Abiraterone

Study of I-131-1095 Radiotherapy in Combination With Enzalutamide in Patients With Metastatic Castration-resistant Prostate Cancer Who Are Chemotherapy Naive and Have Progressed on Abiraterone

EFFECTIVENESS OF HOCHUEKKITO (JAPANESE HERBAL MEDICINE) FOR GENERAL FATIGUE AFTER INTRODUCTION OF ENZALUTAMIDE IN THREE CASES OF CASTRATION-RESISTANT PROSTATE CANCER

(Purpose) Enzalutamide is one of the therapeutic options for castration-resistant prostate cancer (CRPC). However, general fatigue is frequently observed in patients after introduction of enzalutamide. Here, we used the Cancer Fatigue Scale (CFS) to monitor general fatigue after introduction of enzalutamide, and administered the Japanese herbal medicine (Kampo) drug, Hochuekkito, for management of general fatigue. (Materials and methods) Three patients with CRPC were enrolled in this retrospective observational study. The patients were all male, 72, 69, and 88 years old, respectively, and had received previous hormone therapy for CRPC. They complained of general fatigue 2-5 weeks after introduction of enzalutamide. The CFS was divided into three subcategories: physical fatigue, affective fatigue, and cognitive fatigue. Hochuekkito was prescribed for management of general fatigue. Moreover, 31 previous CRPC cases treated in our hospital were divided into a general fatigue group and a non-general fatigue group. The period of enzalutamide prescription was compared among the previous groups and the present three cases to determine the usefulness of Hochuekkito. (Results) In this series, CFS was useful to monitor general fatigue after introduction of enzalutamide. General fatigue after introduction of enzalutamide mainly consisted of physical fatigue, and improved in two of the three cases included in this study. However, enzalutamide was discontinued in one patient due to general fatigue. Fourteen of our 31 previous CRPC cases developed general fatigue after introduction of enzalutamide. The mean periods of enzalutamide prescription were 265.6, 173.2, and 193.0 days in the non-general fatigue, general fatigue, and the present three cases, respectively. The differences among the groups were not significant. (Conclusions) The CFS is useful to monitor general fatigue, including its subcategories, after introduction of enzalutamide in patients with CRPC. The Kampo medicine Hochuekkito may be useful for management of general fatigue in such cases.

Abiraterone plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer: is a question of quality?

Khalaf et al . (1) presented a sub-sequent analysis of a previously conducted phase II trial aimed to compare activity of abiraterone acetate + prednisone (AA + P) versus enzalutamide (E) in more than 200 patients with treatment-naive metastatic castration-resistant prostate cancer (2). In this study, the authors found that AA + P and E showed similar activity in terms of time to prostate-specific antigen (PSA), clinical, or radiographic progression (2).

Efficacy of abiraterone and enzalutamide in patients who had disease progression within twelve months of completing docetaxel for metastatic castration sensitive prostate cancer.

241 Background: Docetaxel is a standard of care for mCSPC. Enzalutamide and abiraterone have been proven to improve survival in metastatic castration-resistant prostate cancer (mCRPC) patients. Little is known about patients who have been treated with docetaxel for mCSPC and subsequent therapeutic responses. This retrospective analysis is to evaluate the response duration of abiraterone and enzalutamide in patients who previously received docetaxel for mCSPC but developed mCRPC within 12 months. Methods: Clinical Trial NCT02649855 enrolled patients with newly diagnosed mCSPC who were treated with standard androgen deprivation therapy (ADT) and docetaxel (75 mg/m2 every 3 weeks for 6 cycles) sequenced with immunotherapy (PROSTVAC) from February 2016 to present. Patients who had progression (based on consecutive PSA rises or imaging) within 1 year of completing docetaxel and went on to subsequent abiraterone/enzalutamide were evaluated. (Note these are different PSA progression criteria than used in CHAARTED, Sweeney, NEJM, 2015). Results: Of the 46 patients evaluated regardless of immunotherapy sequence, 15 (33%) went on subsequent therapy after progression on docetaxel for mCSPC, with 12 patients starting abiraterone/enzalutamide (6 each with high and low volume disease). The median age was 62 (41-83) years. 7/12 patients (58.3%) initiated enzalutamide and 5/12 patients (41.7%) initiated abiraterone. The median duration of treatment for both was 7.12 (1.53–16.0) months, the median time to prostate-specific antigen (PSA) progression was 5.54 (0–15.83) months; 5/12 (41.7%) of patients did not have PSA response. Of note, patients with low volume disease had a median treatment duration of 5.88 months, 3 of them did not have PSA response. Conclusions: These data from a small cohort suggest that patients who have progression within 12 months of completing docetaxel for mCSPC have limited subsequent benefit from enzalutamide or abiraterone. Additional studies are required to determine optimal timing and treatment sequence for patients with mCSPC who rapidly develop mCRPC. Clinical trial information: NCT02649855.

Pretreatment Neutrophil to Lymphocyte Ratio (NLR) Predicts Prognosis for Castration Resistant Prostate Cancer Patients Underwent Enzalutamide.

Introduction Nearly 80% of advanced prostate cancer patients respond to initial androgen deprivation therapy (ADT). However, ADT does not prevent the progression of prostate cancer over the long term, and the disease eventually progresses to castration-resistant prostate cancer (CRPC). Prior to the development of enzalutamide (ENZ) and abiraterone acetate, docetaxel was the only established treatment with life-prolongation for CRPC. ENZ is a second-generation anti-androgen receptor drug that has contributed to improving the prognosis of CRPC. Several studies have reported factors predicting the efficacy of ENZ; however, there are no confirmed biomarkers. The neutrophil-to-lymphocyte ratio (NLR) is an easily calculated biomarker that is associated with the prognosis of several solid malignancies. However, there were few studies investigated NLR for ENZ in patients with mCRPC. We examined the usefulness of the NLR as a predictive tool for ENZ. Methods We retrospectively examined a total of 106 CRPC patients who were treated with ENZ until September 2016 in Yokohama City University Hospital, Yokohama City University Medical Center, and National Cancer Center Hospital East. ENZ was routinely started as a dose of 160 mg per day; the dosage was reduced in some patients due to side effects. Drug holiday for 1-2 weeks or dose reduction to 80-120mg was done and no patients discontinued ENZ treatment due to adverse effects. ENZ was stopped when cancer progression was detected based on PSA elevation, radiographic findings, and deterioration of the patient's performance status. The cut-off NLRs for overall survival (OS) and cancer-specific survival (CSS) were determined based on the receiver-operator curves. Kaplan-Meier curves were used to analyze the factors associated with OS or CSS and a log-rank test was performed. A multivariate analysis was also performed to analyze the factors associated with the prognosis. Results We retrospectively reviewed 106 consecutive CRPC patients who were both treated with ENZ and were able to be counted before ENZ NLR. Cut-off point was 2.14 for both OS and CSS by receiver operator characteristic curve. The patients were then divided into the higher NLR group (≥2.14) and lower NLR group (<2.14). Multivariate analysis showed that NLR and predocetaxel chemotherapy were independent risk factors for both overall and cancer-specific survival. Conclusions The NLR might be a useful biomarker for predicting the prognosis of mCRPC patients who are treated with ENZ.

Management algorithms for prostate-specific antigen progression in prostate cancer: Biochemical recurrence after definitive therapy and progression to non-metastatic castrate-resistant prostate cancer

Current prostate cancer (PCa) guidelines primarily focus on localized or metastatic PCa. A multidisciplinary genitourinary oncology panel determined that additional guidance focusing on monitoring and management of biochemical recurrence (BCR) following radical therapy and non-metastatic castration-resistant prostate cancer (nmCRPC) was warranted. The most up-to-date national and international guidelines, consensus statements, and emerging phase 3 trials were identified and used to inform development of algorithms by a multidisciplinary genitourinary oncology panel outlining optimal monitoring and treatment for patients with non-metastatic PCa. A total of eight major national and international guidelines/consensus statements published since 2015 and three phase 3 trials were identified. Working group discussions among the multidisciplinary genitourinary oncology panel led to the development of two algorithms: the first addressing management of patients with BCR following radical therapy (post-BCR), and the second addressing management of nmCRPC. The post-BCR algorithm suggests consideration of early salvage treatment in select patients and provides guidance regarding observation vs. intermittent or continuous androgen-deprivation therapy (ADT). The nmCRPC algorithm suggests continued ADT and monitoring for all patients, with consideration of treatment with apalutamide or enzalutamide for patients with high-risk disease (prostate-specific antigen [PSA] doubling time of ≤ 10 months). Two treatment algorithms have been developed to guide the management of non-metastatic PCa and should be considered in the context of local guidelines and practice patterns.

Treatment Sequencing of Abiraterone Acetate plus Prednisone and Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer

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Health-related Quality of Life for Abiraterone Plus Prednisone Versus Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer: Results from a Phase II Randomized Trial

BackgroundAbiraterone and enzalutamide are associated with side effects that may impair health-related quality of life (HRQoL). ObjectiveTo assess patient-reported HRQoL, depression symptoms, and cognitive function for abiraterone versus enzalutamide. Design, setting, and participantsWe randomized 202 patients in a phase II study of abiraterone versus enzalutamide for first-line treatment of metastatic castration-resistant prostate cancer (ClinicalTrials.gov: NCT02125357). InterventionPatients completed Functional Assessment of Cancer Therapy—Prostate (FACT-P) and Patient Health Questionnaire-9 (PHQ-9) questionnaires, and Montreal Cognitive Assessment (MoCA) cognitive assessments at baseline and on treatment. Outcome measurements and statistical analysisTo compare the change in FACT-P scores over time between treatment arms, we used a mixed model for repeated measures (MMRM). For FACT-P domains where there was an interaction between the treatment arm and age, we constructed separate models for patients aged <75 and ≥75yr. We compared the proportion of patients with clinically meaningful change from baseline for FACT-P, and the proportion of patients with an abnormal score and median change from baseline for PHQ-9 and MoCA using Fisher's exact test and Mann-Whitney U test. Results and limitationsIn the MMRM analysis, there was a positive test for interaction in the treatment arm by age for total FACT-P (p=0.048). FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the ≥75-yr model (p=0.003), with no difference in the <75-yr model (p>0.9). A higher proportion of patients experienced clinically meaningful worsening with enzalutamide for the physical and functional well-being domains (37% vs 21%, p=0.013; 39% vs 23%, p=0.015). The distribution of change in PHQ-9 scores from baseline favored abiraterone at weeks 4, 8, and 12. These analyses were not prespecified, and results should be considered to be hypothesis generating. ConclusionsPatient-reported outcomes favored abiraterone compared with enzalutamide with differences in FACT-P HRQoL and PHQ-9 depression scores. Differences in the total FACT-P scores were seen only in the elderly patient subgroup. Patient summaryIn this report, we examined the change in patient-reported quality-of-life scores from the start of treatment over time for patients treated with abiraterone versus enzalutamide for metastatic castration-resistant prostate cancer. We found that elderly patients treated with abiraterone had better quality of life over time, with no difference between treatments for the younger subgroup of patients.

Safety of enzalutamide in patients with progressive castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy: a phase II, multicenter, single-arm, open-label study

Background. Enzalutamide, an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway, is approved for patients with metastatic castration-resistant prostate cancer (CRPC). Since the phase III (AFFIRM) pivotal trial did not include Russia patients, this phase II study (NCT02124668) was performed to establish the safety of enzalutamide in patients with progressive CRPC previously treated with docetaxel-based chemotherapy in the Eastern European patients population, including the Russia. Objective: to study safety of enzalutamide in patients with progressive CRPC previously treated with docetaxel-based chemotherapy from Eastern European, including the Russia. Materials and methods . This phase II, multicenter, single-arm, open-label study was conducted at 2 sites in Russia and 2 sites in Georgia. Patients had on going androgen deprivation therapy with a gonadotropin-releasing hormone analogue (agonist or antagonist) or had a prior surgical or chiectomy. Patients completed visits on day 1, week 5, week 13 and subsequently every 12 weeks until they were discontinued from the study. The safety of enzalutamide was assessed through evaluations of adverse events (AEs), serious AEs, blood pressure, heart rate, electrocardiography and laboratory measurements. Results. Thirty patients were enrolled and received enzalutamide treatment (mean age 67.5 years (59–80 years)). Median treatment duration was 271 days (3–968 days). By the end of the study, a total of 23 (76.7 %) patients experienced 68 treatment-emergent AEs (TEAEs). The most frequently reported TEAEs (reported in ≥10 % of patients) were fatigue (n = 7 (23.3 %)), asthenia (n = 6 (20.0 %)), bone pain, metastatic pain, prostatic specific antigen increase from baseline (n = 4 (13.3 %) each) and malignant neoplasm progression (n = 3 (10.0 %)). Most TEAEs were Grade 1 or Grade 2 in severity (35 and 14 events respectively, of a total of 68 AEs). The most frequently reported Grade 3 or higher TEAEs were asthenia (n = 5 (16.7 %)) and bone pain (n = 3 (10.0 %)). Enzalutamide-related TEAEs were experienced by 7 (23.3 %) patients and consisted of the following: fatigue in 3 patients; asthenia in 2 patients; and supraventricular extrasystoles, dizziness, headache, insomnia, pollakiuria and alopecia in 1 patient, each. Six (20.0 %) patients experienced 13 serious TEAEs. The most common serious TEAE was malignant neoplasm progression (n = 3 (1 %)) due to disease progression; all others were single events. Three (10.0 %) patients had died due to serious TEAEs that occurred during the study (2 of prostate cancer progression and 1 of cardiopulmonary and liver failure). No patients experienced an enzalutamide-related Grade 3 or higher TEAEs, an enzalutamide-related serious AEs or an enzalutamide-related TEAEs leading to permanent discontinuation. No notable changes from baseline in clinical laboratory parameters or clinically meaningful abnormalities in vital signs, physical examinations, or electrocardiography were found. No cases of seizures were reported. Conclusion. In this study, enzalutamide in the Eastern European patient population, including the Russia, had a safety profile consistent with that reported in previous enzalutamide studies and no new safety signals were observed.

Safety of continued administration of enzalutamide in patients with prostate cancer who showed benefit from prior exposure: A phase 2 open-label extension study.

303 Background: Enzalutamide (ENZA), an androgen receptor (AR) inhibitor that blocks multiple steps in the AR signaling pathway, is approved for patients (pts) with metastatic castration-resistant prostate cancer. This Phase 2, open-label, extension study (NCT01534052) evaluated long-term safety of continued ENZA administration. Methods: Prostate cancer pts previously treated with ENZA in Phase I studies (NCT01902251; NCT01911728; NCT02225093) continued to receive ENZA 160 mg/day until the investigator considered it no longer beneficial or consent was withdrawn. The primary end point was safety. Baseline data from the parent studies were used. Results: 52 pts were enrolled and received ENZA treatment (median age, 67 years [range, 54–88]). Median treatment duration was 443 days (range, 63–2010) since first administration and 392 days (range, 3–1926) in the extension study. In the extension, 43 pts (82.7%) experienced ≥1 any grade treatment-emergent adverse event (TEAE) with the most common (≥10% of pts) being fatigue (26.9% all grades, 13.5% grade 1, 7.7% grade 2, and 5.8% grade 3); arthralgia and back pain (13.5% each); and diarrhea, hot flush, and decreased appetite (11.5% each). Drug-related TEAEs (investigator assessed) were reported in 27 pts (51.9%) with the most common (≥5% of pts) being fatigue (17.3%); hot flush (11.5%); and diarrhea, hypophosphatemia, and muscle weakness (5.8% each). 17 pts (32.7%) had ≥1 serious TEAE. Eight drug-related serious TEAEs were reported in five pts (malignant neoplasm progression [3.8%]; acute pancreatitis, rectal haemorrhage, cerebrovascular accident, dysarthria, hemiparesis, and hypertensive crisis [1.9% each]). One (1.9%) death due to acute myocardial infarction (not drug-related) and four (7.7%) due to malignant neoplasm progression (two drug-related) were reported. No notable changes from baseline in clinical laboratory parameters or clinically meaningful abnormalities in vital signs, physical examinations, or electrocardiogram were found. Conclusions: Long-term continued ENZA treatment is generally well tolerated, with a safety profile consistent with that previously reported. Clinical trial information: NCT01534052.

Neoadjuvant enzalutamide and androgen deprivation therapy for high-risk prostate cancer: Early results from a feasibility trial.

94 Background: Intensive androgen-targeted therapy improves survival for patients with androgen naive metastatic prostate cancer. Neoadjuvant androgen deprivation therapy (nADT) with abiraterone for localized disease leads to complete responses (pCR) rates of up to 10%. In this study we tested the efficacy of nADT with enzalutamide for patients with high risk, localized disease and the ability of post-treatment multiparametric MRI (mpMRI) to evaluate response. Methods: A single institution trial (NCT02430480) evaluated nADT and enzalutamide 160 mg daily in patients with high risk non-metastatic prostate cancer. Patients underwent MRI-TRUS-guided fusion biopsy at screening and repeat mpMRI followed by radical prostatectomy (RP) after completing six months of therapy. Results: Twenty patients have completed therapy and undergone radical prostatectomy. Clinical characteristics were typical of those with high risk disease: median PSA 8.96 ng/ml (range 2.07-985.9) and clinical stage by mpMRI cT2 (one patient), cT3 (17 patients), or cT4 (2 patients); 7 patients had enlarged pelvic lymph nodes. Following 6 months of therapy, median pre-RP PSA was &lt; 0.02 ng/ml (range &lt; 0.02 – 0.35). On final pathology, 0 patients were upstaged, 5 (25%) were unchanged, and 15 (75%) were downstaged, including 3 (16%) pCR. Four patients were downstaged from N1 to N0. There was little correlation between post-treatment mpMRI tumor volume and pathologic tumor volume. Two patients had radiographic complete responses, one of whom had extensive residual disease. Conclusions: Six months of nADT with enzalutamide has activity in high risk, localized prostate cancer, with a small number of patients having exceptional responses. Standard analysis of mpMRI does not reliably characterize depth of response. Evaluation of molecular characteristics that predict exceptional response or intrinsic resistance is on-going. Patients are being followed for recurrence. Clinical trial information: NCT02430480.

Abstract GS4-07: Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer

Abstract Background: The androgen receptor (AR) is expressed in &amp;gt;75% of hormone receptor (HR)+ tumors. AR signaling has been associated with resistance to endocrine therapy (ET). Aromatase inhibitors (AIs) divert estrogen precursors to androgens; in preclinical models enzalutamide (ENZA) blocked both estrogen- and androgen-mediated growth of HR+ cells. In a phase 1 study of ET+ENZA in breast cancer, doubling the dose of exemestane (EXE) to 50 mg was necessary to restore exposure observed with 25 mg.1 Methods: This placebo (PBO)–controlled phase 2 trial randomized patients (pts) with HR+/HER2-normal advanced/metastatic breast cancer (MBC) to either 25 mg EXE+PBO or 50 mg EXE+160 mg ENZA daily (NCT02007512). Two parallel cohorts enrolled pts who had no prior ET (C1) or who had received 1 prior ET for MBC (C2). Randomization was stratified on resistance to prior ET and prior exposure to AI. Tissue samples for biomarker development were mandatory. Brain metastases or a history of seizure was exclusionary. One prior chemotherapy regimen for MBC was permitted. Response was assessed every 8 weeks for 48 weeks, then every 12 weeks. Crossover to ENZA+EXE was allowed at disease progression. A gene signature–based biomarker (Bmkr) indicating AR signaling predictive of response to ENZA was developed using a training set of RNAseq data from 2/3 of randomized pts and validated using a test set of data from the remaining 1/3 of pts. Progression-free survival (PFS) according to RECIST v1.1 was the primary endpoint in the intent-to-treat (ITT) population and in the Bmkr+ subgroup of each cohort. Secondary endpoints included clinical benefit rate at 24 weeks (CBR24), best overall response, and safety. Results: A total of 247 pts were randomized (C1, n=127; C2, n=120). In C1, 50 pts (39.4%) were Bmkr+; in C2, 35 pts (29.2%) were Bmkr+. Statistically significant improvements in median PFS and CBR24 were observed only in the Bmkr+ population with no prior ET (Table). The most common adverse events (AEs) reported in the ENZA+EXE arms were nausea (39%) in C1 and fatigue (37%) in C2. In C1, 9 pts (15%) and 10 pts (16%) discontinued the study due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. In C2, 11 pts (18%) and 5 pts (8%) discontinued due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. Conclusions: In the first reported randomized trial of ENZA in HR+ MBC, ENZA+EXE was well tolerated with no new safety signals. The study met its primary endpoint in pts with Bmkr+ MBC with no prior ET. 1. Schwartzberg et al. Clin Cancer Res. 2017 Mar 9 [Epub ahead of print]. C1: No Prior ETC2: 1 Prior ET ITTBmkr+ITTBmkr+EXE+ENZA | PBOENZA | PBOENZA | PBOENZA | PBO n=63 | n=64n=24 | n=26n=60 | n=60n=15 | n=20Primary endpointPFS, median, months11.8 | 5.816.5 | 4.33.6 | 3.96.0 | 5.3(95% CI)(7.3, 15.9) | (3.5, 10.9)(11.0, NR) | (1.9, 10.9)(1.9, 5.5) | (2.6, 5.4)(2.3, 26.7) | (1.8, 6.7)Hazard ratio0.820.441.020.55(95% CI)(0.54, 1.26)(0.21, 0.96)(0.66, 1.59)(0.23, 1.36)P value0.36310.03350.92120.1936Secondary endpointCBR24, n (%)39 (62) | 29 (45)20 (83) | 10 (38)12 (20) | 19 (32)6 (40) | 6 (30)(95% CI)(49, 74) | (33, 58)(63, 95) | (20, 59)(11, 32) | (20, 45)(16, 68) | (12, 54)P value0.06090.00120.14430.5374 Citation Format: Krop I, Abramson V, Colleoni M, Traina T, Holmes F, Estevez L, Hart L, Awada A, Zamagni C, Morris P, Schwartzberg L, Chan S, Wheatley D, Gucalp A, Biganzoli L, Steinberg J, Gianni L, Trudeau M, Tudor IC, Markova D, Barry E, Tarazi J, Stewart R, Winer E, Yardley DA. Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-07.

Toxicity profile characteristics of novel androgen-deprivation therapy agents in patients with prostate cancer: a meta-analysis

ABSTRACTBackground: To investigate the toxicity profile characteristics of abiraterone acetate and enzalutamide to see if they are of critical clinical value.Methods: Prospective studies were identified by searching the PubMed, EMBASE, Cochrane Library, and American Society of Clinical Oncology Meeting abstracts. Randomized clinical trials that evaluate abiraterone acetate or enzalutamide in patients with prostate cancer were included. The risk ratio (RR) of adverse events (AEs) was calculated for each trial along with appropriate 95% CI using fixed- or random-effects methods.Results: Ten studies (5 abiraterone acetate, and 5 enzalutamide studies) were included in the meta-analysis. Use of abiraterone acetate was associated with an increased risk of all-grade adverse effects (RR = 1.01, 95% CI: 1.01–1.02) and high-grade adverse effects (RR = 1.29, 95% CI: 1.15–1.45). Also, there was a significantly higher incidence of some individual adverse effects (e.g. liver-function test abnormalities, arthralgia, cardiac adverse effects, diarrhea, oedema, hypertension and hypokalemia). Treatment with enzalutamide did not increase the risk of all-grade adverse effects and high-grade adverse effects, but there was a significantly higher incidence of some individual adverse effects (e.g. back pain, fatigue, hot flush and hypertension).Conclusions: Both abiraterone acetate and enzalutamide have toxicity profile characteristics that need to be recognized. Understanding the toxicity profile characteristics of both drugs could promote decision making in clinical use.

Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration-resistant prostate cancer (CRPC).

Two androgen receptor (AR)-targeted therapies, enzalutamide and abiraterone acetate plus prednisone (abiraterone), have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). Many patients respond to these agents, but both de novo and acquired resistance are common. The authors characterized resistant phenotypes that emerge after treatment with abiraterone or enzalutamide. Patients who received abiraterone or enzalutamide in the course of routine clinical care were consented for serial blood collection. A proprietary system (CellSearch) was used to enumerate and enrich circulating tumor cells (CTCs). RNA-sequencing (RNA-seq) was performed on pools of up to 10 epithelial cell adhesion molecule (EpCAM)-positive/CD45-negative CTCs. The impact of gene expression changes observed in CTCs between patients who responded or were resistant to abiraterone/enzalutamide therapies was further explored in a model cell line system. RNA-seq data from CTCs identified mutations commonly associated with CRPC as well as novel mutations, including several in the ligand-binding domain of AR that could facilitate escape from AR-targeted agents. Ingenuity pathway analysis of differentially regulated genes identified the transforming growth factor β (TGFβ) and cyclin D1 (CCND1) signaling pathways as significantly upregulated in drug-resistant CTCs. Transfection experiments using enzalutamide-sensitive and enzalutamide-resistant LNCaP cells confirmed the involvement of SMAD family member 3, a key mediator of the TGFβ pathway, and of CCND1 in resistance to enzalutamide treatment. The current results indicate that RNA-seq of CTCs representing abiraterone and enzalutamide sensitive and resistant states can identify potential mechanisms of resistance. Therapies targeting the downstream signaling mediated by SMAD family member 3 (SMAD3) and CCND1, such as cyclin-dependent kinase 4/cyclin-dependent kinase 6 inhibitors, could provide new therapeutic options for the treatment of antiandrogen-resistant disease. Cancer 2018;124:1216-24. © 2017 American Cancer Society.

Dutch Economic Value of Radium-223 in Metastatic Castration-Resistant Prostate Cancer.

BackgroundThe treatment of metastatic castration-resistant prostate cancer has changed with the introduction of radium-223, cabazitaxel, abiraterone and enzalutamide. To assess value for money, their cost effectiveness in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective was investigated.MethodsA cost-effectiveness analysis was conducted using efficacy, symptomatic skeletal-related event and safety data obtained from indirect treatment comparisons. Missing skeletal-related event data for cabazitaxel were conservatively assumed to be identical to radium-223. A Markov model combined these clinical inputs with Dutch-specific resource use and costs for metastatic castration-resistant prostate cancer treatment from a societal perspective. Total quality-adjusted life-years and costs in 2017 euros were calculated over a 5-year (lifetime) time horizon.ResultsRadium-223 resulted in €6092 and €4465 lower costs and 0.02 and 0.01 higher quality-adjusted life-years compared with abiraterone and cabazitaxel, respectively, demonstrating dominance of radium-223. Sensitivity analyses reveal a 64% (54%) chance of radium-223 being cost effective compared with abiraterone (cabazitaxel) at the informal €80,000 willingness-to-pay threshold. Compared with enzalutamide, radium-223 resulted in slightly lower quality-adjusted life-years (−0.06) and €7390 lower costs, revealing a 61% chance of radium-223 being cost effective compared with enzalutamide. The lower costs of radium-223 compared with abiraterone and enzalutamide are driven by lower drug costs and prevention of expensive skeletal-related events. Compared with cabazitaxel, the lower costs of radium-223 are driven by lower costs of the drug, administration and adverse events.ConclusionRadium-223 may be a less costly treatment strategy offering similar gains in health benefits compared with abiraterone, cabazitaxel and enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective.Electronic supplementary materialThe online version of this article (doi:10.1007/s40258-017-0350-x) contains supplementary material, which is available to authorized users.

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

BackgroundEnzalutamide 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. ObjectiveTo 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 participantsMulticentre, 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. InterventionPatients received enzalutamide 160mg/d orally. Outcome measurements and statistical analysisThe 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 limitationsOverall, 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. ConclusionsEnzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment. Patient summaryPatients 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.

Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial

BackgroundThe effect of enzalutamide on health-related quality of life (HRQoL) in the PREVAIL trial in chemotherapy-naïve men with metastatic castration-resistant prostate cancer was analyzed using the generic EQ-5D instrument.MethodsPatients received oral enzalutamide 160 mg/day (n = 872) or placebo (n = 845). EQ-5D index and EQ-5D visual analogue scale (EQ-5D VAS) scores were evaluated at baseline, week 13, and every 12 weeks until week 61 due to sample size reduction thereafter. Changes on individual dimensions were assessed, and Paretian Classification of Health Change (PCHC) and time-to-event analyses were conducted.ResultsWith enzalutamide, EQ-5D index and EQ-5D VAS scores declined more slowly versus placebo and time to diverge from full health was prolonged. Average decline in EQ-5D index (−0.042 vs. –0.070; P < .0001) and EQ-5D VAS (−1.3 vs. –4.4; P < .0001) was significantly smaller with enzalutamide. There were significant (P < .05) between-group differences favoring enzalutamide in Pain/Discomfort to week 37, Anxiety/Depression at week 13, and Usual Activities at week 25, but no significant differences for Mobility and Self-care. The PCHC analysis showed more enzalutamide patients reporting improvement than placebo patients at weeks 13, 25, and 49 (all P < .05) and week 37 (P = .0512). Enzalutamide was superior (P ≤ .0003) to placebo for time to diverge from full health and time to first deterioration on Pain/Discomfort and Anxiety/Depression dimensions.ConclusionsThis in-depth post hoc analysis showed that enzalutamide delayed HRQoL deterioration and had beneficial effects on several HRQoL domains, including Pain/Discomfort and the proportion of patients in full health, compared with placebo, and may help to support future analyses of this type.Trial registrationNCT01212991

Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS.

A phase II trial of enzalutamide in patients with androgen receptor positive (AR+) ovarian, primary peritoneal or fallopian tube cancer and one, two, or three prior therapies.

TPS5610 Background: Approximately 75% of women with epithelial ovarian cancer (OC) present with advanced disease. Most of these women will ultimately recur and require life-long treatment for their cancer. Well tolerated therapies for treatment in the recurrent setting are needed. The AR is expressed in greater than 60% of cases of OC and is more prevalent than the estrogen or progesterone receptor. All past clinical studies of AR inhibition in OC have focused on unselected populations of heavily pretreated women; however preclinical data suggests that AR expression decreases in OC cells with increasing lines of therapy. Enzalutamide is a small molecule androgen receptor-antagonist that is FDA approved for treatment of prostate cancer and is currently being investigated as treatment for breast and ovarian cancer. Methods: This is a phase II, single-institution trial of enzalutamide 160mg po QD in patients with AR+ ovarian, fallopian tube or primary peritoneal cancer. Eligible patients must be found to have greater than or equal to 5% AR staining by IHC on FFPE tumor tissue and been treated with only 1,2 or 3 prior cytotoxic therapies. Patients must have RECIST 1.1 defined measurable disease. Enrolled patients are treated with enzalutamide until progression of disease or unacceptable toxicity. The primary endpoint is to estimate the proportion of women who achieve a complete or partial response by RECIST 1.1 criteria or survive progression free for at least 6 months. Secondary objectives include the retrieval of optional tumor biopsies at time of progression to evaluate the effect of enzalutamide on AR expression and to observe the effect of enzalutamide on serum testosterone and estradiol levels. This study will enroll 58 patients at Memorial Sloan Kettering Cancer Center and its regional sites. The study utilizes a safety lead-in phase and a two-stage design. The first patient enrolled in April 2015. The safety lead-in phase has been completed. The prespecified activity goal for the first stage was met; second stage accrual began in October 2016. Thus far, 35 patients have initiated treatment. Clinical trial information: NCT01974765.

A randomized study of enzalutamide in patients with localized prostate cancer undergoing active surveillance (ENACT).

TPS5097 Background: Prostate cancer (PC) patients (pts) who select active surveillance (AS) are a heterogeneous population with varying risks for disease progression. Studies have estimated that approximately 31–42% of pts electing AS have experienced disease progression (pathological or therapeutic) over 1.8 and 2.3 years. There is no evidence-based pharmacological intervention which has effectively lessened this progression event. Pharmacological intervention with enzalutamide (ENZ), an androgen receptor inhibitor approved for treatment of metastatic castration-resistant PC, may lessen this progression. The aims of this study are to evaluate the efficacy of ENZ versus AS alone for delaying time to progression in pts with clinically localized PC undergoing AS. This study examines the effects of ENZ on progression in a subset of pts with low- or intermediate-risk PC who would otherwise elect an AS protocol. Methods: This is a multicenter, randomized, open-label study (NCT02799745). Eligibility criteria include histologically confirmed prostate adenocarcinoma within 6 months of screening, low or intermediate risk PC (T1c−T2c, prostate-specific antigen [PSA] &lt; 20, N0, M0, Gleason score ≤7 [3+4 pattern only]), Eastern Cooperative Oncology Group status ≤2 and estimated life expectancy &gt; 5 years. Exclusion criteria include any prior PC intervention. Pts will be randomized to receive open-label oral ENZ 160 mg/day once daily or to AS during the 1-year study treatment period. After the first year, all pts will be followed for one additional year with no other intervention. All pts will undergo prostate biopsy at 1 and 2 years. The primary end point is time to PC progression (pathological or therapeutic). Secondary end points include safety, incidence of negative biopsies for cancer at 1 and 2 years, percentage of cancer positive cores at 1 and 2 years, time to PSA progression, incidence of secondary rise in serum PSA, and quality-of-life questionnaires. Exploratory end points include biomarker assessment and genomic analysis. Study enrolment commenced in June 2016, with study completion expected in March 2019. Planned total enrolment is 222 pts from ~60 United States/Canadian sites. Clinical trial information: NCT02799745.