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Resistance to second-generation androgen receptor antagonists in prostate cancer

Abstract

The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. SG-ARAs provide similar therapeutic benefit to abiraterone, a potent CYP17 inhibitor, and do not require the co-administration of prednisone. Despite considerable improvements in clinical outcomes in the settings of both castration sensitivity and castration resistance, the durability of clinical response to the SG-ARAs enzalutamide, apalutamide and darolutamide, similar to abiraterone, is limited by inevitable acquired resistance. Genomic aberrations that confer resistance to SG-ARAs or provide potential alternative treatment modalities have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K–AKT–mTOR and Wnt–β-catenin pathways. To combat resistance, researchers have explored approaches to optimizing the utility of available treatments, as well as the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2 and HIF1α. Ongoing research to establish predictive biomarkers for the treatment of tumours with resistance to SG-ARAs led to the approval of the PARP inhibitors olaparib and rucaparib in pre-treated metastatic castration-resistant prostate cancer. The results of ongoing studies will help to shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes.

Key points

  • Second-generation androgen receptor antagonists (SG-ARAs) have substantially improved outcomes in patients with advanced and/or metastatic prostate cancer.

  • Acquired resistance to SG-ARA treatment limits the effectiveness of therapy and can be conferred through multiple mechanisms, including genomic alterations of the androgen receptor (AR), DNA damage repair (DDR), phosphoinositide 3-kinase–protein kinase B–mammalian target of rapamycin (PI3K–AKT–mTOR), Wnt–β-catenin and neuroendocrine differentiation pathways.

  • Novel therapies targeting the AR have sought to overcome numerous mechanisms of resistance, including AR amplification, AR splice variation, AR point mutations and AR bypass facilitated via the glucocorticoid receptor.

  • Alternative therapeutic approaches to AR targeting to overcome SG-ARA resistance include investigational agents targeting cell-signalling pathways (e.g. PI3K–AKT–mTOR), DNA damage repair, angiogenesis, epithelial–mesenchymal transition and AR-independent lineage plasticity.

  • To minimize SG-ARA resistance, optimization of available and investigational treatments in a patient-specific manner are being considered to maximize clinical outcomes in patients with prostate cancer.

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Fig. 1: AR-mediated acquired resistance mechanisms to SG-ARAs and potential treatments under investigation.
Fig. 2: Non-AR-mediated acquired resistance to SG-ARAs and potential treatments under investigation.
Fig. 3: Examples of treatment implementation strategies for advanced prostate cancer.

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Acknowledgements

The authors’ work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD, USA (ZIA BC 010453). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organization imply endorsement by the US Government.

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K.T.S., C.H.C. and A.D.R.H. researched data for the article, W.D.F., K.T.S. and C.H.C. wrote the article and W.D.F., K.T.S, A.D.R.H. and C.H.C. reviewed and edited the manuscript and made a substantial contribution to the discussion of content.

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Correspondence to William D. Figg.

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Supplementary information

Glossary

Castration-resistant prostate cancer

(CRPC). A diagnosis of prostate cancer with disease progression (defined by PSA progression in the non-metastatic setting (nmCRPC), and radiographic progression in the metastatic setting (mCRPC)) despite castration levels of testosterone, achieved through long-standing androgen deprivation therapy or via orchiectomy (surgical removal of the testes).

Biomarkers

Biological molecules isolated from patients with cancer (in blood, tumour, urine etc.) that are informative of molecular features of the disease and could be utilized to better understand response to treatment.

Epigenetic reprogramming

Changes in transcription and modifications to chromatin, resulting in loss of characteristics of the original cell, and acquisition of a new molecular signature, irrespective of genomic alterations.

Cross-talk

Cellular processes in a tumour cell that can be activated by two or more cell-signalling pathways, which can result in unattenuated signalling via inhibition of only one of these pathways and/or amplification of the transcriptional pattern.

Homologous recombination repair

(HRR). DNA metabolic process involved in template-dependent repair or tolerance of complex DNA damages (such as DNA gaps, DNA double-strand breaks). Genomic alterations to numerous proteins involved in this process, including BRCA1/2, have been noted to be predictive markers for poly(ADP-ribose) polymerase inhibitor therapy.

Synthetic lethality

A co-occurrence of multiple genetic events that results in cell death, whereas each event occurring independently would be tolerable for cell survival. A frequently characterized ‘synthetic lethal’ combination in prostate cancer comprises a tumour cell with a DNA damage repair mutation treated with a poly(ADP-ribose) polymerase inhibitor.

Immunologically cold

A term referencing tumours in which few to no immune cells are present and so they do not readily respond to immunotherapeutic treatment (e.g. PD1/PDL1 inhibition).

Microsatellite instability

(MSI). Observed differences of tumour cells in short tandem repeat DNA sequences (1–6 base pairs) in comparison with the inherited genome, frequently associated with defective mismatch repair. Tumours with high MSI have been proven to be more susceptible to immunotherapy, notably pembrolizumab.

WNT–β-catenin pathway

A cell-signalling pathway that implicates important cellular functions, including stem cell regeneration and organogenesis. β-catenin, in addition to its activation via the canonical pathway, can specifically interact with the androgen receptor (AR) to enhance gene transcription.

Basket trials

Clinical trials that select a specific biomarker–treatment pairing and screen patients in a histologically agnostic approach (that is irrespective of tumour origin) in search of the specific biomarker to determine eligibility for one of the available biomarker–treatment arms.

Umbrella trials

Clinical trials that prospectively screens patients with a pre-specified cancer to assign a molecular signature to determine enrolment and/or placement into pre-specified treatment arms.

N-terminal domain of the AR

The non-ligand-binding domain of the androgen receptor (AR), as opposed to the C-terminal domain containing the ligand-binding domain. The N-terminal domain is conserved in full-length AR, splice variant AR, and AR with ligand-binding domain mutations, and provides a potential advantage owing to non-competitive inhibition.

Antisense oligonucleotide

A small single-stranded nucleic acid designed to bind to a specific RNA sequence in tumour cells to bring about gene silencing and result in tumour cell growth inhibition.

PROteolysis TArgeting Chimera

(PROTAC). A heterobifunctional molecule designed with two ligands, one to bind a target protein and the other to bind E3 ubiquitin ligase, connected by a linker. The function is to facilitate the degradation of target protein via the ubiquitin–proteasome system.

Bromodomain and extraterminal (BET) chromatin reader

A family of proteins that serve as epigenetic readers of acetylated histones and can regulate gene transcription.

PI3K–AKT–mTOR pathway

An intracellular cell signalling pathway that promotes metabolism, growth, proliferation, survival and angiogenesis following activation via an extracellular signal under normal conditions. In prostate cancer, this pathway can become dysregulated, most frequently via the absence of phosphatase and tensin homologue (PTEN), to promote tumorigenesis, and is thus a viable target for drug development.

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Schmidt, K.T., Huitema, A.D.R., Chau, C.H. et al. Resistance to second-generation androgen receptor antagonists in prostate cancer. Nat Rev Urol 18, 209–226 (2021). https://doi.org/10.1038/s41585-021-00438-4

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