Use Of Enzalutamide Research Articles

The sequential use of abiraterone and enzalutamide in metastatic castrate resistant prostate cancer patients: Experience from seven U.K. centers.

125 Background: Phase III studies have demonstrated survival benefits from abiraterone (Abi), and enzalutamide (Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is now available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enz has recently become available, via the UK cancer drugs fund (CDF), for progressive disease post docetaxel, prior to exposure to Abi. There has been no randomised trial on sequential usage of Enz post-Abi. We therefore, report the experience of hospitals in Coventry, Cardiff, and five centers in Birmingham. Methods: We searched the pharmacy database for patients who have received Enz as part of an early access scheme, and identified 79 patients who started treatment between the August 2012 and April 2013. A detailed notes review was carried out of these patients. Results: Median age was 74 (range of 55 to 87). All patients had received hormone androgen deprivation therapy and taxane chemotherapy (docetaxel and/or cabazitaxel) 75 patients had received previous Abi, 62 of these patients receiving Abi as the last treatment prior to Enz. The mean time to progression (TTP) for Abi in these 62 patients was 37.44 weeks (range 4 to 104). At the time of submission 55 patients had stopped Enz due to prostate-specific antigen progression with a mean TTP of 15.87 weeks and 28 patients had died. Conclusions: The AFFIRM study demonstrated TTP of 36 weeks in patients post-docetaxel. In this audit of patients receiving Enz post-Abi the TTP was only 15.87 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. Trials are underway comparing Abi alone or in combination with Enz which may improve efficacy.

Enzalutamide After Docetaxel and Abiraterone Therapy in Metastatic Castration-Resistant Prostate Cancer

Enzalutamide is a novel antiandrogen which is approved for the treatment of metastatic, castration-resistant prostate cancer (mCRPC) after taxane-based chemotherapy. The efficacy of enzalutamide after the sequence docetaxel and abiraterone is not proven. Thirty-five mCRPC patients in the German compassionate use program, who received enzalutamide after progression with taxane-based chemotherapy and abiraterone were prospectively evaluated. The endpoints of the study were overall survival, radiologic progression-free survival and safety. The median treatment duration on enzalutamide was 2.8months. The median overall survival was 7.5months [95% confidence interval (CI) 4.7-10.3] while median progression-free survival assessed by imaging was 3.1months (95% CI 1.4-4.8). The most common toxicities of all grades were anemia and weight loss. Although the results are limited by a small patient number, the consecutive use of enzalutamide and abiraterone after taxane-based chemotherapy shows a modest clinical activity. Thus, sequence therapy alternating between chemotherapy and antihormonal drugs might be a more promising approach in mCRPC treatment.

Further analysis of PREVAIL: enzalutamide use in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.

PREVAIL was a phase III multinational, double-blind, placebo-controlled trial that enrolled chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC), which showed remarkable improvement in co-primary endpoints with an overall 81% reduction in the risk of radiographic progression, as well as 29% reduction in the risk of death in favor of the enzalutamide arm over placebo. All secondary endpoints including time to subsequent chemotherapy initiation and prostate specific antigen (PSA) progression were in favor of the enzalutamide arm. The results of PREVAIL shows the utility of enzalutamide that would likely soon expand the indication to asymptomatic or minimally symptomatic men with mCRPC not previously treated with chemotherapy.

Application of a novel method weighing drug costs against survival in castrate-resistant prostate cancer cancer.

271 Background: In the last few years, 5 new anticancer drugs have been introduced for the treatment of castration-resistant prostate cancer (CRPC). The objective was to apply a simplified methodology of weighing drug costs against overall survival (OS) in CRPC. Methods: Estimated cost in United Sates (US) dollars of an entire treatment course of an evaluated drug was divided by previously reported median OS gain over control. An initial survey of 45 drugs demonstrated that the maximal cost/OS/day gain was $757. Accordingly, a scale of crude scores was constructed with a 0% assigned to a cost/OS gain greater than $1,000 and 100% to a cost/OS gain of $1. Value scores were calculated after adjusting for quality of life (QoL), adverse events (AEs), and specialized administration and preparation (AP). Results: The lowest cost/OS gain and highest value score were demonstrated by generic docetaxel. Enzalutamide in previously-treated and abiraterone in chemo-naïve and treated patients x 6 months showed cost/OS gain lower than that of docetaxel but significantly higher than cabazitaxel. Pricing of sipuleucel-T based on cost of the entire course partly accounted for its highest cost/OS and lowest scores. Extending abiraterone and enzalutamide treatment to 12 months increased cost/OS gain and decreased scores. Conclusions: Methodology was proposed to weigh drug cost against OS/day gain with and without adjustment for QoL, AEs, and AP. Results in CRPC tend to support use of docetaxel, abiraterone, and enzalutamide rather than cabazitaxel and sipuleucel-T. Varying drug indications and different populations within the CRPC spectrum preclude direct drug comparison.

Inhibition of constitutively active Stat3 reverses enzalutamide resistance in LNCaP derivative prostate cancer cells

Use of enzalutamide has improved the treatment of advanced prostate cancer. However, resistance to enzalutamide can develop frequently in initial responders. This study aimed to test whether overexpression of IL-6 and constitutive activation of Stat3 in prostate cancer cells increase resistance to enzalutamide. Sensitivity of prostate cancer cells to enzalutamide was tested using cell growth assays and clonogenic assays. Quantitative reverse transcription-PCR, ELISA, and Western blotting were performed to detect expression levels of IL-6, c-Myc, survivin, and AR. Expression of Stat3 was downregulated using siRNA specific to Stat3. ChIP assay was performed to examine recruitment of AR to the PSA promoter. Prostate cancer cells expressing autocrine IL-6 are resistant to enzalutamide and autocrine IL-6 leads to constitutive activation of Stat3 and its target genes. Down regulation of Stat3 led to an increase in sensitivity of prostate cancer cells to enzalutamide. Overexpression of constitutively active Stat3 in prostate cancer cells induced resistance to enzalutamide treatment. Constitutively active Stat3 also enhanced the recruitment of AR to PSA promoter which could not be disrupted by enzalutamide. The Stat3 inhibitor AG490 reversed enzalutamide resistance in prostate cancer cells, while combination treatment with enzalutamide and AG490 significantly inhibited cell growth and induced cell apoptosis. This study demonstrates that the autocrine IL-6 pathway induces enzalutamide resistance in prostate cancer cells via the constitutive activation of Stat3. Co-targeting IL6-Stat3 pathway with enzalutamide may be utilized for treatment of advanced prostate cancer.

Evidence for the efficacy of enzalutamide in postchemotherapy metastatic castrate-resistant prostate cancer

The treatment of metastatic castrate-resistant prostate cancer (mCRPC) has evolved rapidly with the recent approval of a number of treatments and agents, including docetaxel, sipuleucel T, abiraterone, cabazitaxel, and enzalutamide. Enzalutamide (previously MDV-3100) is a novel oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. The randomized phase III AFFIRM study demonstrated significant improvements in a number of efficacy endpoints, including the primary endpoint of overall survival and secondary endpoints of progression-free survival, and time to prostate-specific antigen progression in patients with progressive mCRPC who had received prior treatment with docetaxel. Enzalutamide was well tolerated and there were comparable incidences of grade 3 or greater adverse events reported for the enzalutamide and placebo control arms in AFFIRM. Unlike some other treatments for mCRPC, enzalutamide does not require administration with steroids. The ongoing randomized phase III PREVAIL trial will investigate the efficacy and safety of enzalutamide in chemotherapy-naïve patients with mCRPC. Additional trials are investigating the use of enzalutamide in a number of disease settings.

The sequential use of abiraterone and enzalutamide (MDV3100) in castrate resistant prostate cancer patients: Experience from Birmingham, United Kingdom.

e16048 Background: Phase III studies have demonstrated survival benefits from abiraterone1 (Abi), and Enzalutamide2 (MDV3100; Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enzalutamide (Enz) is available, via early access scheme, for progressive disease post docetaxel, regardless of prior Abi exposure. There has been no randomised trial on sequential usage of Enz post Abi. We therefore report our experience. Methods: We searched our pharmacy database for patients who have received Enz and identified 51 patients who started treatment between the 2nd August 2012 and 10thJanuary 2013. A detailed notes review was carried out of these patients. Results: Median age was 76 (range 55-87) years. All patients had received androgen deprivation therapy and Docetaxel. 46 patients had received previous Abi, 38 of patients’ receiving Abi as the last treatment prior to Enz. At the time of submission 10 patients had stopped Enz due to PSA progression with a mean TTP of 15 weeks (range 7-22) and 6 patients had died; 2 from disease progression (mean TTP 3.5 weeks). For the 30 patients still on Enz, the mean duration of treatment was 16.47 weeks (range 4-27). 33 patients didn't report any significant side effects associated with Enz treatment. The most common side effect was fatigue (23.6%); 3 patients (6%) experiencing G3 fatigue. Other reported side effects included diarrhoea (4%), nausea (6%), confusion (6%), anxiety (6%), depression (6%), hallucinations (2%) and insomnia (2%). 3 patients (6%) had Enz stopped due to G3 fatigue. Conclusions: The AFFIRM study demonstrated TTP of 8.3 months (36 weeks) in patients post-docetaxel2. In this audit the TTP of patients receiving Enz post-Abi was 15 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. However, longer follow-up of the 30 patients currently taking Enz is required. The number of patients experiencing G3 fatigue was the same as reported in AFFIRM, but there were a surprising number of patients experiencing psychiatric side-effects.