An FDA Review of Drug Development in Nonmetastatic Castration-resistant Prostate Cancer

Brave, Michael; Weinstock, Chana; Brewer, Jamie R.; Chi, Dow-Chung; Suzman, Daniel L.; Cheng, Joyce; Zhang, Lijun; Sridhara, Rajeshwari; Ibrahim, Amna; Kluetz, Paul G.; Pazdur, Richard; Beaver, Julia A.

doi:10.1158/1078-0432.ccr-19-3835

Cited by 21 publications

(10 citation statements)

References 7 publications

(8 reference statements)

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“…Since the CRPC growth depends on AR-signaling, targeting the AR is beneficial also in CRPC [ 25 ]. Important examples are the recently clinically approved AR antagonists Enzalutamide (Enz), Apalutamide (Apa) and Darolutamide that are used in therapy of mCRPC, mCSPC, and nmCRPC, respectively [ 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Kokal

Mirzakhani

Pungsrinont

et al. 2020

Cancers

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The androgen receptor (AR) plays a leading role in the control of prostate cancer (PCa) growth. Interestingly, structurally different AR antagonists with distinct mechanisms of antagonism induce cell senescence, a mechanism that inhibits cell cycle progression, and thus seems to be a key cellular response for the treatment of PCa. Surprisingly, while physiological levels of androgens promote growth, supraphysiological androgen levels (SAL) inhibit PCa growth in an AR-dependent manner by inducing cell senescence in cancer cells. Thus, oppositional acting ligands, AR antagonists, and agonists are able to induce cellular senescence in PCa cells, as shown in cell culture model as well as ex vivo in patient tumor samples. This suggests a dual AR-signaling dependent on androgen levels that leads to the paradox of the rational to keep the AR constantly inactivated in order to treat PCa. These observations however opened the option to treat PCa patients with AR antagonists and/or with androgens at supraphysiological levels. The latter is currently used in clinical trials in so-called bipolar androgen therapy (BAT). Notably, cellular senescence is induced by AR antagonists or agonist in both androgen-dependent and castration-resistant PCa (CRPC). Pathway analysis suggests a crosstalk between AR and the non-receptor tyrosine kinase Src-Akt/PKB and the PI3K-mTOR-autophagy signaling in mediating AR-induced cellular senescence in PCa. In this review, we summarize the current knowledge of therapeutic induction and intracellular pathways of AR-mediated cellular senescence.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Kokal

Mirzakhani

Pungsrinont

et al. 2020

Cancers

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“…More specifically, the Prostate Cancer Clinical Trials Working Group 3 defined nmCRPC as a progressively rising prostate-specific antigen (PSA) level, namely a 25% PSA increase from nadir (starting PSA ≥ 1.0 ng/mL), with a minimum increase of 2 ng/mL despite a tor-mediated transcription [15,16]. Between 2018 and 2019, the Food and Drug Administration (FDA) approved three second-generation ARi for nmCRPC [17]. These drugs are orally administered and their characteristics are summarized in Table 1.…”

Section: Definition Of Nmcrpcmentioning

confidence: 99%

“…In addition, the formers bind directly to the ligand-binding domain of the androgen receptor, inhibit its nuclear translocation, inhibit DNA binding, and impede androgen receptor-mediated transcription [15,16]. Between 2018 and 2019, the Food and Drug Administration (FDA) approved three second-generation ARi for nmCRPC [17]. These drugs are orally administered and their characteristics are summarized in Table 1.…”

Section: Introductionmentioning

confidence: 99%

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Novel Treatment Strategy Using Second-Generation Androgen Receptor Inhibitors for Non-Metastatic Castration-Resistant Prostate Cancer

Chung

2021

Biomedicines

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Non-metastatic castration-resistant prostate cancer (nmCRPC) is defined by a progressively rising prostate-specific antigen level, despite a castrate level of testosterone, in the absence of obvious radiologic evidence of metastatic disease on conventional imaging modalities. As a significant proportion of patients with nmCRPC develop metastatic diseases, the therapeutic goals of physicians for these patients are to delay metastasis development, preserve quality of life, and increase overall survival (OS). Since 2018, the treatment of nmCRPC has changed dramatically with the introduction of second-generation androgen receptor inhibitors, such as enzalutamide (ENZA), apalutamide (APA), and darolutamide (DARO). These drugs demonstrated substantial improvements in metastasis-free survival (MFS) and OS in phase Ⅲ randomized clinical trials. In addition, these drugs have an excellent safety profile, preserve quality of life, and can delay disease-related symptoms. A recently published indirect meta-analysis reported that APA and ENZA showed better findings in MFS and that DARO had relatively fewer adverse effects. However, in the absence of a direct comparison, careful interpretation is required. Thus, APA, ENZA, and DARO should be considered the new standard drugs for treating nmCRPC.

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“…Brave et al [21] showed similarities between these studies, such as phase III, doubleblind trials with 2:1 randomization of drug versus placebo; patients with PSADT ≤ 10 months (subgroup <6 months and ≥6 months); the allowed inclusion of pelvic adenopathies of up to 2 cm in the SPARTAN and ARAMIS studies; the authorized inclusion of patients who had or were receiving treatment with bone protective agents; conventional imaging techniques that were performed at baseline and every 16 weeks (thoraco-abdomino-pelvic CT or MRI and bone scintigraphy) to determine the absence of metastasis and disease progression, based on the response evaluation criteria in solid tumors (RECIST), version 1.1 [22]; and the main endpoints were MFS, overall survival (OS), and time to initiation of cytotoxic therapy.…”

Section: Pivotal Clinical Trialsmentioning

confidence: 99%

Treatment Landscape of Nonmetastatic Castration-Resistant Prostate Cancer: A Window of Opportunity

López-Campos

Conde-Moreno

Arcos

et al. 2021

JPM

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The treatment for nonmetastatic castration-resistant prostate cancer (nmCRPC) is a highly unmet medical need. The classic treatment approach for these patients—androgen deprivation therapy (ADT) alone—until metastatic progression is now considered suboptimal. Several randomized phase III clinical trials have demonstrated significant clinical benefits—including significantly better overall survival (OS)—for treatments that combine ADT with apalutamide, enzalutamide, and darolutamide. As a result, these approaches are now included in treatment guidelines and are considered a standard of care. In the present article, we discuss the changing landscape of the management of patients with nmCRPC.

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An FDA Review of Drug Development in Nonmetastatic Castration-resistant Prostate Cancer

Cited by 21 publications

References 7 publications

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Novel Treatment Strategy Using Second-Generation Androgen Receptor Inhibitors for Non-Metastatic Castration-Resistant Prostate Cancer

Treatment Landscape of Nonmetastatic Castration-Resistant Prostate Cancer: A Window of Opportunity

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