Is there an anti-androgen withdrawal syndrome for enzalutamide?

Klot, Christoph A. von; Kramer, Mario W.; Böker, Alena; Herrmann, Thomas; Peters, Inga; Kuczyk, Markus A.; Ligges, Uwe; Gschwend, Jürgen E.; Retz, Margitta; Schmid, Sebastian; Stenzl, Arnulf; Schwentner, Christian; Todenhöfer, T.; Stöckle, Michael; Ohlmann, Carsten-Henning; Azone, Ines; Mager, René; Bartsch, Georg; Haferkamp, Axel; Heidenreich, Axel; Piper, Charlotte; Merseburger, Axel S.

doi:10.1007/s00345-014-1288-3

Cited by 13 publications

(11 citation statements)

References 30 publications

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“…Unfortunately, no factors were found to be adequate predictors of response. In the second study, von Klot and coworkers reported the occurrence of EWS in 31 patients whose data were collected from 6 different centers in Germany (von Klot et al 2014). No PSA reduction was observed in any of the 31 patients, and authors concluded that if existent, an EWS was at least very rare for enzalutamide in patients with mCRPC after taxane-based chemotherapy and without a clinical role in this setting.…”

Section: Enzalutamide Withdrawal Syndrome (Ews)mentioning

confidence: 99%

Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer

Leone

Tucci

Buttigliero

et al. 2018

Endocrine-Related Cancer

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Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with hormone-sensitive prostate cancer treated with combined androgen blockade therapy. It is defined by prostate-specific antigen value reduction, occasionally associated with a radiological response, that occurs 4-6 weeks after first-generation antiandrogen therapy discontinuation. New-generation hormonal therapies, such as enzalutamide and abiraterone acetate, improved the overall survival in patients with metastatic castrationresistant prostate cancer, and recent trials have also shown the efficacy of abiraterone in hormone-sensitive disease. In the last few years, several case reports and retrospective studies suggested that the withdrawal syndrome may also occur with these new drugs. This review summarizes literature data and hypothesis about the biological rationale underlying the syndrome and its potential clinical relevance, focusing mainly on newgeneration hormonal therapies. Several in vitro studies suggest that androgen receptor gain-of-function mutations are involved in this syndrome, shifting the antiandrogen activity from antagonist to agonist. Several different drug-specific point mutations have been reported. The association of the withdrawal syndrome for enzalutamide and abiraterone needs confirmation by additional investigations. However, new-generation hormonal therapies being increasingly used in all stages of disease, more patients may experience the syndrome when stopping the treatment at the time of disease progression, although the clinical relevance of this phenomenon in the management of metastatic castration-resistant prostate cancer remains to be defined.

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Section: Enzalutamide Withdrawal Syndrome (Ews)mentioning

confidence: 99%

Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer

Leone

Tucci

Buttigliero

et al. 2018

Endocrine-Related Cancer

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“…Im Gegensatz zu anderen Antiandrogenen wie Bicalutamid hat Enzalutamid keine agonistische Wirkung. In diesem Zusammenhang wird die Frage eines Enzalutamid Withdrawal Syndroms (EWS) für dieses neue Antiandrogen kontrovers diskutiert: In vitro, in vivo sowie klinische Daten sprechen für das mögliche Vorliegen eines EWS, welches allerdings in dem bisher untersuchten Setting nach Chemotherapie in weniger als 10 % der Fälle vorkommen dürfte und derzeit klinisch keine Relevanz hat [6,7]. In der AFFIRM- …”

Section: Enzalutamidunclassified

Kastrationsresistentes Prostatakarzinom 2015

et al. 2015

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Prostate cancer is still the most common urological cancer of the elderly man. In some patients, a metastatic prostate cancer arises which may remain a stable disease for years with palliative antiandrogen therapy. On average, after 3-4 years, affected men develop a PSA rise and disease progression with the formation of a so-called castration-resistant disease. 5 years ago cytotoxic chemotherapy with docetaxel was the only life-prolonging treatment option in this situation. In the last 5 years, the results of randomised phase III studies have led to the approval of 5 new agents for the treatment of metastatic castration resistant prostate cancer (mCRPC). The results and approval status of the substances, Abiraterone, Enzalutamide, Cabazitaxel, Sipuleucel-T and radium-223 are described below. In addition, some aspects of sequential therapy and possible future molecular approaches are discussed.

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“…It has previously been described for antiandrogens such as flutamide and bicalutamide, but information regarding enzalutamide withdrawal is currently limited von Klot et al 2014avon Klot et al , 2014b. Two recent reports, based on 30 patients and 31 patients with mCRPC, respectively, suggest that antiandrogen withdrawal syndrome with enzalutamide appears to be rare with the Datapoints are means and whiskers depict standard deviations.…”

Section: Other Observationsmentioning

confidence: 99%

“…Adverse event, n (%) Enzalutamide (n = 800) Placebo (n = 399) currently available follow up and withdrawal timeframes [Phillips, 2014;Rodriguez-Vida et al 2014;von Klot et al 2014a].…”

Section: Other Observationsmentioning

confidence: 99%

An update on enzalutamide in the treatment of prostate cancer

Merseburger

Haas

Klot

2014

Therapeutic Advances in Urology

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Abstract:Enzalutamide is an oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. In the randomized phase III AFFIRM study, significant improvements in survival versus placebo were observed when enzalutamide was used as a treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) following prior treatment with docetaxel. Additional benefits included significant delay in time to first skeletal-related event, and improvement in several measures of pain and health-related quality of life. Treatment effects were consistent across all prespecified subgroups. The phase III PREVAIL study evaluated enzalutamide versus placebo in patients with mCRPC who had not received chemotherapy. Enzalutamide significantly decreased the risk of radiographic progression and death. There were also significant improvements in all secondary and prespecified exploratory endpoints, including delayed initiation of chemotherapy, reduction in risk of first skeletal-related event and a high percentage of patients with objective response compared with placebo. Enzalutamide was also studied in hormone naïve patients (as monotherapy) in a small, open-label phase II study in patients with prostate cancer who were eligible for androgen-deprivation therapy. A prostate-specific antigen (PSA) response, defined as ⩾80% decline in PSA level from baseline at week 25, was achieved in 92.5% of patients. Long-term follow up is ongoing. Despite differences between these three trials, enzalutamide displayed a favorable safety profile in all three patient populations. Similar rates of adverse events between the enzalutamide and placebo groups were observed in AFFIRM and PREVAIL, with fatigue, diarrhea, back pain and hot flashes being more common with enzalutamide than with placebo. Hypertension was reported at a higher rate in the enzalutamide group than in the placebo group in PREVAIL. Breast-related disorders associated with enzalutamide treatment were also reported in the Monotherapy trial. Few seizures were reported in any trial. Enzalutamide is being studied in several early disease state populations.

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Is there an anti-androgen withdrawal syndrome for enzalutamide?

Cited by 13 publications

References 30 publications

Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer

Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer

Kastrationsresistentes Prostatakarzinom 2015

An update on enzalutamide in the treatment of prostate cancer

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