Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer

Davis, Ian D.; Martin, Andrew; Stockler, Martin R.; Begbie, Stephen; N., Kim; Chowdhury, Simon; Coskinas, Xanthi; Frydenberg, Mark; Hague, Wendy; Horvath, Lisa G.; Joshua, Anthony M.; Lawrence, Nicola; Marx, Gavin; McCaffrey, John; McDermott, Ray; McJannett, Margaret; North, Scott; Parnis, Francis; Parulekar, Wendy R.; Pook, David; Reaume, M. Neil; Sandhu, Shahneen; Tan, Alvin; Tan, Thean Hsiang; Thomson, Alastair; Tu, Emily; Vera‐Badillo, Francisco; Williams, Scott; Yip, Sonia; Zhang, Alison; Zielinski, Robert; Sweeney, Christopher J.

doi:10.1056/nejmoa1903835

Cited by 1,188 publications

(956 citation statements)

References 20 publications

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“…The panel's recommendation was made irrespective of metastatic burden (86% consensus). Recent data from the ARCHES, ENZAMET, and TITAN studies suggest clinical benefit with enzalutamide and apalutamide in this setting as well 61–63 . US FDA approval for these agents in mHSPC is pending.…”

Section: Resultsmentioning

confidence: 99%

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Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines

et al. 2020

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Background For specific clinical indications, androgen deprivation therapy (ADT) will induce disease prostate cancer (PC) regression, relieve symptoms and prolong survival; however, ADT has a well‐described range of side effects, which may have a detrimental effect on the patient's quality of life, necessitating additional interventions or changes in PC treatment. The risk‐benefit analysis for initiating ADT in PC patients throughout the PC disease continuum warrants review. Methods A 14‐member panel comprised of urologic and medical oncologists were chosen for an expert review panel, to provide guidance on a more judicious use of ADT in advanced PC patients. Panel members were chosen based upon their academic and community experience and expertise in the management of PC patients. Four academic members of the panel served as group leaders; the remaining eight panel members were from Large Urology Group Practice Association practices with proven experience in leading their advanced PC clinics. The panel members were assigned to four separate working groups, and were tasked with addressing the role of ADT in specific PC settings. Results This article describes the practical recommendations of an expert panel for the use of ADT throughout the PC disease continuum, as well as an algorithm summarizing the key recommendations. The target for this publication is all providers (urologists, medical oncologists, radiation oncologists, or advanced practice providers) who evaluate and manage advanced PC patients, regardless of their practice setting. Conclusion The panel has provided recommendations for monitoring PC patients while on ADT, recognizing that PC patients will progress despite testosterone suppression and, therefore, early identification of conversion from castrate‐sensitive to castration resistance is critical. Also, the requirement to both identify and mitigate side effects of ADT as well as the importance of quality of life maintenance are essential to the optimization of patient care, especially as more combinatorial therapeutic strategies with ADT continue to emerge.

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Section: Resultsmentioning

confidence: 99%

“…9 The panel felt that T levels should be ENZAMET, and TITAN studies suggest clinical benefit with enzalutamide and apalutamide in this setting as well. [61][62][63] US FDA approval for these agents in mHSPC is pending.…”

Section: The Role Of Adt In Salvage Therapymentioning

confidence: 99%

Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines

et al. 2020

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“…Enzalutamide is a second‐generation antiandrogen with multiple mechanisms of action, including inhibition of androgen receptor (AR)–testosterone ligand binding, AR nuclear translocation, and DNA transactivation. The ARCHES (a study of enzalutamide plus ADT vs placebo plus ADT in patients with mHSPC) and ENZAMET (enzalutamide in first‐line ADT for metastatic prostate cancer) trials recently reported the therapeutic benefits of enzalutamide combined with ADT compared with ADT alone and ADT plus a non‐steroidal antiandrogen, respectively. There was a 61% delay to radiographic progression of disease or death (HR 0.39, 95% CI 0.3–0.5) regardless of disease volume or prior docetaxel treatment and a 33% improvement in OS (HR 0.67, 95% CI 0.52–0.86) .…”

Section: Dosage Adverse Events and Key Practice Points Associated Wimentioning

confidence: 99%

“…Enzalutamide is associated with a low but significant risk of seizures. Furthermore, clinically significant fatigue and cognition issues are well‐recognised and reported in 25% and 14% of patients, respectively . This point of difference compared to other AR‐pathway inhibitors is likely to be particularly relevant in older patients.…”

Section: Dosage Adverse Events and Key Practice Points Associated Wimentioning

confidence: 99%

Novel agents for metastatic hormone‐sensitive prostate cancer – a practice guide for urologists

et al. 2019

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“…Consequently, the development and FDA approval of agents that more effectively target androgen signaling, including enzalutamide (ENZ, Xtandi; an AR antagonist) (3)(4)(5), has expanded the therapeutic options for CRPC. Nevertheless, even these approaches cannot durably control tumor growth and there is considerable variability in the nature and duration of responses between different patients (3,6,7). Thus, alternative therapeutic strategies that enhance response to ADT, and thereby prevent or delay PCa progression to CRPC, are essential.…”

Section: Introductionmentioning

confidence: 99%

DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

Nassar

Mah

Dehairs

et al. 2019

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Fatty acidβ -oxidation (FAO) is the main bioenergetic pathway in prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, which encodes the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival.DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown in PCa cells selectively inhibited β -oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation in vivo.Mechanistically, targeting of DECR1 caused cellular accumulation of linoleic acid, enhanced mitochondrial oxidative stress and lipid peroxidation, and ferroptosis. These findings implicate PUFA oxidation via DECR1 as a previously unexplored facet of FAO that promotes survival of PCa cells.

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Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer

Cited by 1,188 publications

References 20 publications

Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines

Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines

Novel agents for metastatic hormone‐sensitive prostate cancer – a practice guide for urologists

DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

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