Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201)

Borgmann, Hendrik; Lallous, Nada; Özistanbullu, Deniz; Beraldi, Eliana; Paul, Naman; Dalal, Kush; Fazli, Ladan; Haferkamp, Axel; Lejeune, Pascale; Cherkasov, Artem; Gleave, Martin

doi:10.1016/j.eururo.2017.08.012

Cited by 77 publications

(59 citation statements)

References 10 publications

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“…Indeed, alternative mechanisms for AR pathway activation have been identified as engendering tumor growth. Novel AR antagonists may be able to target growth mediated by AR mutations (eg, darolutamide delayed the growth of enzalutamide‐resistant prostate cancer harboring mutated AR in a preclinical system) . BRCA2 , ATM , and TP53 ctDNA mutations also have been associated with rapid resistance in the setting of enzalutamide or abiraterone …”

Section: Discussionmentioning

confidence: 99%

“…Novel AR antagonists may be able to target growth mediated by AR mutations (eg, darolutamide delayed the growth of enzalutamide-resistant prostate cancer harboring mutated AR in a preclinical system). 30 BRCA2, ATM, and TP53 ctDNA mutations also have been associated with rapid resistance in the setting of enzalutamide or abiraterone. 29,31 Four patients in the current study (patients 7, 9, 35, and 45) had serial testing performed on 3 different dates at variable intervals.…”

Section: Discussionmentioning

confidence: 99%

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Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer

Sonpavde

Agarwal

Pond

et al. 2019

Cancer

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Background Because cell‐free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration‐resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. Methods Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer‐associated genes. Clinical factors, therapy information, failure‐free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. Results Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta‐1 (CTNNB1), and AT‐rich interactive domain‐containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure‐free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. Conclusions ctDNA frequently was detected in this large cohort of “real‐world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer

Sonpavde

Agarwal

Pond

et al. 2019

Cancer

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“…Darolutamide strongly impairs androgen binding to the AR and androgen‐induced nuclear translocation . It shows strong in vivo efficacy in the vertebral cancer of the prostate (VCaP) xenograft model which expresses high levels of AR wild type and of the V7 splice variant, and in the enzalutamide‐resistant MR49F model which contains the AR mutations F877L and T878A …”

Section: Introductionmentioning

confidence: 99%

“…12 It shows strong in vivo efficacy in the vertebral cancer of the prostate (VCaP) xenograft model which expresses high levels of AR wild type and of the V7 splice variant, 12 and in the enzalutamide-resistant MR49F model which contains the AR mutations F877L and T878A. 15 Here, we determined the activity of darolutamide in several cellular assays and prostate cancer models. Strong inhibition of transactivation, N-and C-terminal domain interaction and homodimerization were seen for AR wild type and W742C/L mutants.…”

Section: Introductionmentioning

confidence: 99%

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Sugawara

Baumgart

Nevedomskaya

et al. 2019

Intl Journal of Cancer

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Darolutamide is a novel androgen receptor (AR) antagonist with a distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using cell‐based transactivation assays, we demonstrate that darolutamide, its diastereomers and its main metabolite keto‐darolutamide are strong, competitive antagonists for AR wild type, and also for several mutants identified in prostate cancer patients for which other AR antagonists show reduced antagonism or even agonism. Darolutamide, its two diastereomers and main metabolite are also strong antagonists in assays measuring AR N/C interaction and homodimerization. Molecular modeling suggests that the flexibility of darolutamide allows accommodation in the W742C/L mutated AR ligand‐binding pocket while for enzalutamide the loss of the important hydrophobic interaction with W742 leads to reduced AR interaction. This correlates with an antagonistic pattern profile of coregulator recruitment for darolutamide. In vitro efficacy studies performed with androgen‐dependent prostate cancer cell lines show that darolutamide strongly reduces cell viability and potently inhibits spheroid formation. Also, a marked down‐regulation of androgen target genes paralleled by decreased AR binding to gene regulatory regions is seen. In vivo studies reveal that oral dosing of darolutamide markedly reduces growth of the LAPC‐4 cell line‐derived xenograft and of the KuCaP‐1 patient‐derived xenograft. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.

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“…Enzalutamide (20 mg/kg body weight) or vehicle was administered daily through oral gavage for consecutive 2 to 3 weeks, starting from day 15 (the subcutaneous and orthotopical models) or day 1 (the intratibial model) post injection. The dosing was chosen based on previous publication (16). We conducted all the statistical analyses in these three experiments using a linear mixed-effect model and found that the C4-2B cells responded differently to enzalutamide in the different microenvironments.…”

Section: Resultsmentioning

confidence: 99%

Enzalutamide-induced PTH1R-mediated TGFBR2 decrease in osteoblasts contributes to resistance in prostate cancer bone metastases

Cao

Meng

et al. 2019

Preprint

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Over 80% of prostate cancer (PCa) patients in the United States die with bone metastases.Second-line hormonal therapies, such as enzalutamide, improve overall survival in about 50% of patients with bone metastases, but almost all responsive patients eventually develop enzalutamide resistance. Our study showed that although enzalutamide significantly inhibited the tumor growth of subcutaneously or orthotopically grafted PCa C4-2B cells, it had no effect on the bone lesion development when C4-2B tumors were grafted in the bone, suggesting a crucial role of the microenvironment in enzalutamide resistance in PCa bone metastasis. We found that enzalutamide significantly decreased the amount of the TGFBR2 (TGF-β type II receptor) in osteoblasts, both in vitro and in patient samples. The osteoblast-specific knockout of Tgfbr2 significantly induced bone metastasis. We showed that the enzalutamide-induced TGFBR2 decrease in osteoblasts was mediated by increased PTH1R (parathyroid hormone/parathyroid hormone-related peptide receptor), which resulted in TGFBR2 degradation, and that blocking PTH1R rescued the TGFBR2 decrease. Furthermore, we found that PTH1R up-regulation by enzalutamide was correlated with increased Pth1r promoter occupancy by transcription factor NR2F1. Our findings highlight a potential enzalutamide-resistance mechanism through TGFBR2 decrease in osteoblasts, thus suggesting future PTH1R-blocking approaches to overcome enzalutamide resistance in PCa bone metastasis.

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Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201)

Cited by 77 publications

References 10 publications

Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer

Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Enzalutamide-induced PTH1R-mediated TGFBR2 decrease in osteoblasts contributes to resistance in prostate cancer bone metastases

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