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BIOMARKER:

AR H875Y

i
Other names: AR, AIS, DHTR, HUMARA, NR3C4, SBMA, SMAX1, Androgen receptor
Entrez ID:
Related biomarkers:
2ms
Developing a Novel Enzalutamide-Resistant Prostate Cancer Model via AR F877L Mutation in LNCaP Cells. (PubMed, Curr Protoc)
We also assessed the efficacy of target protein degraders (TPDs), such as ARV-110 and ARV-667, in both models, and the corresponding validation data are also included here.
Preclinical • Journal
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AR (Androgen receptor)
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AR mutation • AR T878A • AR F877L • AR H875Y • AR F877L + AR T878A
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Xtandi (enzalutamide capsule) • bavdegalutamide (ARV-110)
6ms
Characterizing longitudinal molecular changes in ctDNA in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2024)
Our study revealed dynamic shifts in genetic mutations in pts with mCRPC following ARSi, PARPi and taxanes. Additionally, we highlight the prognostic significant of ctDNA burden in mCRPC. These data can help inform personalized sequential tx strategies for pts with mCRPC.
Clinical • BRCA Biomarker • PARP Biomarker • Circulating tumor DNA • Metastases
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PALB2 (Partner and localizer of BRCA2) • CDK12 (Cyclin dependent kinase 12)
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PALB2 mutation • AR T878A • AR amplification • AR F877L • AR H875Y • AR L702H
1year
Associations between androgen-directed treatments and AR mutational landscapes in the circulating tumor DNA of a real-world metastatic prostate cancer cohort. (ASCO 2023)
AR mutations have implications for clinical decision making and drug development in patients treated with abiraterone and/or enzalutamide. >1n (%).
Real-world evidence • Clinical • Circulating tumor DNA • Real-world • Metastases
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AR mutation • AR T878A • AR F877L • AR H875Y • AR L702H
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Tempus xF Assay
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Xtandi (enzalutamide capsule) • abiraterone acetate
1year
A partially open conformation of an androgen receptor ligand-binding domain with drug-resistance mutations. (PubMed, Acta Crystallogr F Struct Biol Commun)
Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them...Additional structural studies suggest that both the L702H and F877L mutations are important for conformational changes. This structural variability in the AR LBD could affect ligand binding as well as the resistance to antagonists.
Journal
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AR (Androgen receptor)
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AR T878A • AR expression • AR F877L • AR H875Y • AR L702H • AR F877L + AR T878A
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Xtandi (enzalutamide capsule) • Erleada (apalutamide) • pruxelutamide (GT0918)
over1year
HSK38008: An oral AR-V7 degrader for metastatic castration-resistant prostate cancer (AACR 2023)
The androgen deprivation therapy (ADT) alone and its combination with hormone therapy that block AR signaling (e.g., enzalutamide or abiraterone) are effective treatments for advanced prostate cancer. No animal was found dead or moribund and no test article-related changes in clinical signs,body weights, food consumption, ophthalmologic examinations, clinical pathology parameters, sperm analysis, urinalysis, organ weights, histopathology. In conclusion, HSK38008 is a promising oral AR-V7 degrader with better efficacy than enzalutamide and ARV-110 in AR and AR-V7 positive, and potential AR mutants mCRPC.
Late-breaking abstract • Metastases
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AR (Androgen receptor)
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AR mutation • AR T878A • AR splice variant 7 • AR-V7 positive • AR H875Y • AR T878S
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Xtandi (enzalutamide capsule) • abiraterone acetate • bavdegalutamide (ARV-110) • HSK38008
over1year
Androgen receptor (AR) mutations in men with metastatic castration-resistant prostate cancer (mCRPC): Incidence and natural history. (ASCO-GU 2023)
Two early phase trials investigating CYP11A1 inhibitors - CYPIDES (ODM208, NCT03436485) and STESIDES (ODM209, NCT03878823) - recruited mCRPC patients with and without pre-specified AR LBD mutation...Overall, 212 (78%), 202 (74%), and 240 (88%) patients had received previous abiraterone, enzalutamide, and docetaxel respectively... AR LBD mutations were detected in ctDNA in 25% of men with advanced mCRPC treated with at least one ARSI. Their incidence was associated with a longer duration of treatment with enzalutamide and a longer time from CRPC and prostate cancer diagnosis. >
Metastases
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AR (Androgen receptor) • STING (stimulator of interferon response cGAMP interactor 1)
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AR mutation • AR T878A • AR F877L • AR H875Y • AR L702H
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Guardant360® CDx • FoundationOne® Liquid CDx
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docetaxel • Xtandi (enzalutamide capsule) • abiraterone acetate • opevesostat (ODM-208) • ODM-209
over1year
Real-world assessment of AR-LBD mutations in metastatic castration-resistant prostate cancer. (ASCO-GU 2023)
In this large database, the overall detection rate of activating AR-LBD mutations in men with mCRPC undergoing ctDNA analysis was 21%, and increased with prior use of 2nd generation ARPi (abiraterone and enzalutamide). Men with AR-LBD mutations were more likely to harbor other alterations relevant to tumor progression. These findings inform on the ctDNA prevalence and impact of AR-LBD mutations in a real-world dataset of mCRPC.
Real-world evidence • Clinical • BRCA Biomarker • Real-world • Metastases
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TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
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PTEN mutation • AR mutation • AR T878A • AR F877L • AR H875Y • AR L702H • AR T878S
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Guardant360® CDx
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Xtandi (enzalutamide capsule) • abiraterone acetate
over1year
A phase 2 expansion study of ARV-766, a PROTAC androgen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2023)
Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140.
P2 data • Metastases
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AR (Androgen receptor)
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AR mutation • AR T878A • AR H875Y • AR L702H • AR wild-type
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Xtandi (enzalutamide capsule) • abiraterone acetate • ARV-766
almost2years
Structural and molecular insights into the mechanism of resistance to enzalutamide by the clinical mutants in androgen receptor (AR) in castration-resistant prostate cancer (CRPC) patients. (PubMed, Int J Biol Macromol)
The proteins' motion and FEL further validated the aforementioned findings where the wild type reported different dynamic features than the mutant complexes. In conclusion, this study provides a structural basis for the resistance to Enzalutamide, which can be used to design novel effective drugs using structure-based and rationale approaches.
Journal
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AR (Androgen receptor)
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AR T878A • AR F877L • AR H875Y • AR F877L + AR T878A
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Xtandi (enzalutamide capsule)
almost2years
Androgen receptor mutations for precision medicine in prostate cancer. (PubMed, Endocr Relat Cancer)
Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Therefore, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy.
Review • Journal
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AR (Androgen receptor)
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AR mutation • AR overexpression • AR T878A • AR amplification • AR F877L • AR H875Y • AR L702H • AR F877L + AR T878A
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Xtandi (enzalutamide capsule) • abiraterone acetate
2years
PROTAC Shrinks Mutated Prostate Tumors. (PubMed, Cancer Discov)
The most clinically advanced proteolysis-targeting chimera, bavdegalutamide, seems to work best against two molecularly defined subtypes of advanced prostate cancer. According to phase I/II trial data presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium, the androgen receptor degrader most commonly shows antitumor activity among patients with T878X or H875Y mutations.
Journal
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AR (Androgen receptor)
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AR H875Y
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bavdegalutamide (ARV-110)
over2years
Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2022)
In phase 1, pts with mCRPC and disease progression after =2 prior therapies (enzalutamide and/or abiraterone required) received ARV-110 orally once or twice daily (QD or BID) in sequential cohorts (3 + 3 dose escalation design). ARV-110, a novel AR protein degrader, demonstrates clinical activity in a post-NHA, heavily pretreated mCRPC pt population, with greatest PSA50 activity and RECIST responses in pts with AR T878 and/or H875 mutations, likely representing a particularly ARV-110–sensitive population. ARV-110 merits further investigation in pts with mCRPC.
P1/2 data
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AR (Androgen receptor)
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AR mutation • AR T878A • AR splice variant 7 • AR H875Y • AR L702H • AR wild-type • AR-V7 mutation
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Xtandi (enzalutamide capsule) • abiraterone acetate • bavdegalutamide (ARV-110)
over2years
Implications of androgen receptor (AR) alterations identified by genomic testing of tissue and blood from advanced prostate cancer (aPC) patients (pts). (ASCO-GU 2022)
AR mutations in post-ARTA group were seen at similar rates regardless of prior docetaxel exposure (14.3% vs 18.0%, p = 0.46) and following first abiraterone vs enzalutamide/apalutamide exposure (48.6% vs 48.3%, p = 1.0). AR mutations, unlike amplifications, were associated with shorter TTP on abiraterone. Genomic testing should be considered before second line ARTA.
Clinical
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AR (Androgen receptor)
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AR mutation • AR T878A • AR amplification • AR H875Y • AR L702H
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docetaxel • Xtandi (enzalutamide capsule) • abiraterone acetate • Erleada (apalutamide)
over2years
Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2022)
In phase 1, pts with mCRPC and disease progression after =2 prior therapies (enzalutamide and/or abiraterone required) received ARV-110 orally once or twice daily (QD or BID) in sequential cohorts (3 + 3 dose escalation design). ARV-110, a novel AR protein degrader, demonstrates clinical activity in a post-NHA, heavily pretreated mCRPC pt population, with greatest PSA50 activity and RECIST responses in pts with AR T878 and/or H875 mutations, likely representing a particularly ARV-110–sensitive population. ARV-110 merits further investigation in pts with mCRPC.
P1/2 data
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AR (Androgen receptor)
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AR mutation • AR T878A • AR splice variant 7 • AR H875Y • AR L702H • AR wild-type • AR-V7 mutation
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Xtandi (enzalutamide capsule) • abiraterone acetate • bavdegalutamide (ARV-110)