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Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial. In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991. Median treatment duration was 16·6 months (IQR 10·1–21·1) in the enzalutamide group and 4·6 months (2·8–9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1–13·9) in the enzalutamide group and 5·6 months (5·5–5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54–0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score (327 [40%] of 826 vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p<0·0001). Median time to progression in BPI-SF pain at its worst was 5·7 months (95% CI 5·6–5·7) in the enzalutamide group and 5·6 months (5·4–5·6) in the placebo group (HR 0·62 [95% CI 0·53–0·74]; p<0·0001). Progression of pain at its worst was less common in the enzalutamide group than in the placebo group at week 13 (220 [29%] of 769 vs 257 [42%] of 610; p<0·0001), but not at week 25 (225 [32%] of 705 vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5–not reached) and 31·3 months (95% CI 23·9–not reached) in the placebo group (HR 0·72 [95% CI 0·61–0·84]; p<0·0001). In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Astellas Pharma and Medivation.

The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years, with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had non-castration levels of testosterone and prostate-specific antigen (PSA) of 2 ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160 mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT01302041. 67 men were enrolled into the study. 62 patients (92·5%, 95% CI 86·2–98·8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n=24), fatigue (n=23), nipple pain (n=13), and hot flush (n=12), all of which were of mild to moderate severity. Nine patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related. Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression, and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in non-castrate men with prostate cancer. Astellas Pharma Inc, Medivation Inc.

Abstract Background This was a first-in-human, phase I, dose-escalation study evaluating the safety, pharmacokinetics, and preliminary efficacy of zavondemstat (TACH101), an epigenetic targeting inhibitor of KDM4 histone demethylase, in patients with heavily pre-treated advanced/metastatic cancers. Patients and Methods Patients received zavondemstat orally on a weekly schedule in 28-day cycles. Dose escalation followed a Bayesian optimal interval design and explored both intermittent and continuous dosing. The primary objectives were to assess safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase II dose (RP2D). Secondary objectives included pharmacokinetics and radiographic response per Response Evaluation Criteria in Solid Tumors, version 1.1. Results Thirty patients were enrolled across 6 dose cohorts. MTD was not reached at the maximum dose tested. The most common treatment-related adverse events (TRAEs) were diarrhea (12%), fatigue (7%), decreased appetite (7%), nausea (7%), and hyponatremia (7%). All TRAEs were grade 1 or 2. No serious TRAEs or DLTs were reported. Of 23 response-evaluable patients, 10 (44%) achieved stable disease (SD). Two patients (9%) had SD ≥ 6 months, including a patient with castration-resistant prostate cancer and a patient with leiomyosarcoma. A third patient (leiomyosarcoma) receiving ongoing treatment with zavondemstat under compassionate use has had SD for 6+ months. Zavondemstat demonstrated a dose-proportional exposure profile with a half-life of about 1.5 hours. There was no to minimal drug accumulation observed. Conclusions Zavondemstat was very well tolerated and showed encouraging preliminary clinical benefit in heavily pretreated patients with advanced cancer. Continued evaluation of zavondemstat is warranted.

SummaryBackground. EPI-506 is the first of a new class of drugs targeting the N-terminal domain (NTD) of the androgen receptor (AR), potentially overcoming known resistance mechanisms to androgen receptor pathway inhibitors (ARPIs) among men with metastatic castration resistant prostate cancer (mCRPC). Methods. Patients with mCRPC who had progressed on prior ARPI were enrolled in this phase 1 open-label, adaptive 3 + 3 dose escalation study. The primary outcome was safety and tolerability of oral EPI-506. Secondary objectives included determination of the maximal tolerated dose (MTD), pharmacokinetic profile, and antitumor efficacy. Results. 28 mCRPC patients were enrolled into 7 dose cohorts of EPI-506 ranging from 80-3600 mg given once daily and 1800 mg given twice daily. Six DLTs occurred in 4 patients; Grade 4 elevated amylase; Grade 3 abdominal pain; Grade 3 elevated ALT and Grade 3 elevated AST; Grade 2 nausea and Grade 1 vomiting which resulted in study drug intake of < 75% of the expected dose during the DLT assessment period. The most common drug-related adverse events included diarrhea, nausea and fatigue. Six patients had a PSA decline not meeting PSA response criteria. The study was terminated prior to reaching the MTD due to poor oral bioavailability. Conclusions. This phase 1 trial established the safety of EPI-506 and provides proof of concept for targeting the AR NTD. Next generation compounds with improved bioavailability and potency are in clinical development.