Drug safety is a barrier to the discovery and development of new androgen receptor antagonists

Foster, William; Car, Bruce D.; Shi, Hong; Lévesque, Paul; Obermeier, Mary; Gan, Jinping; Arezzo, Joseph C.; Powlin, Stephanie S.; Dinchuk, Joseph; Balog, Aaron; Salvati, Mark; Attar, Ricardo M.; Gottardis, Marco M.

doi:10.1002/pros.21263

Cited by 108 publications

(87 citation statements)

References 14 publications

(21 reference statements)

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“…It has a higher efficacy than enz, as 30 mg/kg per day has the same therapeutic effect as 100 mg/kg per day enz (Clegg et al 2012). Moreover, due to the lower required dosage of ARN-509, it has a lower tendency to induce seizures, a typical side effect of antiandrogens from the bic class (Foster et al 2011).…”

Section: Antiandrogensmentioning

confidence: 99%

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Androgen receptor antagonists for prostate cancer therapy

Helsen¹,

Broeck²,

Voet³

et al. 2014

Endocrine-Related Cancer

120

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Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

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Section: Antiandrogensmentioning

confidence: 99%

“…Both the first-and second-generation NSAAs demonstrate an identical off-target on GABAA receptors in the brain, leading to seizures (Foster et al 2011). In light of this, ARN-509 has been developed, which has a reduced passage through the blood-brain barrier.…”

Section: Antiandrogensmentioning

confidence: 99%

Androgen receptor antagonists for prostate cancer therapy

Helsen¹,

Broeck²,

Voet³

et al. 2014

Endocrine-Related Cancer

120

View full text Add to dashboard Cite

show abstract

“…However, whether pharmacologic ADT with LHRH-A plus AR antagonists can trigger effective antitumor immunity still remains controversial (18). Additionally, nonsteroidal AR antagonists are identified as belonging to a class of antiandrogens that cause undesirable symptoms, such as seizures, likely mediated through antagonism of the central nervous system (CNS)-based g-aminobutyric acid type A (GABA-A) receptor by an off-target mechanism (19). Whether these off-target effects impact immune regulation remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse

Liang

et al. 2016

Sci. Transl. Med.

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Surgical and medical androgen deprivation therapy (ADT) is a cornerstone for prostate cancer treatment, but relapse usually occurs. We herein show that orchiectomy synergizes with immunotherapy, whereas the more widely used treatment of medical ADT involving androgen receptor (AR) antagonists suppresses immunotherapy. Furthermore, we observed that the use of medical ADT could unexpectedly impair the adaptive immune responses through interference with initial T cell priming rather than in the reactivation or expansion phases. Mechanistically, we have revealed that inadvertent immunosuppression might be potentially mediated by a receptor shared with g-aminobutyric acid. Our data demonstrate that the timing and dosing of antiandrogens are critical to maximizing the antitumor effects of combination therapy. This study highlights an underappreciated mechanism of AR antagonist-mediated immunosuppression and provides a new strategy to enhance immune response and prevent the relapse of advanced prostate cancer.

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“…This increase in seizure incidence is believed to be due to the ability of enzalutamide to cross the blood-brain barrier and inhibit GABA channels, with convulsions being observed to be dose-dependent when administered above the therapeutic range in animal studies. 52 Thus, caution should be used when administering enzalutamide in patients with a known history of seizures.…”

Section: Enzalutamide: a Second-generation Ar Antagonistmentioning

confidence: 99%

Contemporary agents in the management of metastatic castration-resistant prostate cancer

Kapoor

Shayegan³

et al. 2016

CUAJ

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Docetaxel-based chemotherapy has been the standard of care for metastatic castration-resistant prostate cancer (mCRPC) since 2004. Over the past few years, there has been a significant paradigm shift in the treatment landscape of this disease. A deeper understanding of prostate cancer biology, along with the development of novel agents has created hope towards treating chemotherapy-naïve and resistant disease. Following the implementation of docetaxel as the first-line therapy for mCRPC, five novel therapies have demonstrated survival benefit in mCRPC. Cabazitaxel, abiraterone acetate, and enzalutamide are three agents recently approved for the treatment of mCRPC, having shown overall survival benefit in patients previously treated with docetaxel, while both abiraterone acetate and enzalutamide have also shown promise in the pre-docetaxel setting. Sipuleucel-T has shown overall survival benefit in asymptomatic mCRPC, while radium-223 provides survival benefit to patients with mCRPC who are symptomatic from their skeletal metastases in both docetaxel-naïve patients and post-docetaxel patients. Denosumab, an anti-RANKL antibody, has been approved for the prevention of skeletal-related events in patients with prostate cancer bone metastases. This review examines the phase 3 trials supporting the use of theses novel agents in the treatment of mCRPC. While these agents provide incremental increases in patient survival, further study to determine the best choice, combination, and/or sequencing of administration is still necessary.

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Drug safety is a barrier to the discovery and development of new androgen receptor antagonists

Cited by 108 publications

References 14 publications

Androgen receptor antagonists for prostate cancer therapy

Androgen receptor antagonists for prostate cancer therapy

Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse

Contemporary agents in the management of metastatic castration-resistant prostate cancer

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