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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Huggins, C. & Hodges, C. V. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J. Clin. 22, 232–240 (1972).
Gomella, L. G. Effective testosterone suppression for prostate cancer: is there a best castration therapy? Rev. Urol. 11, 52–60 (2009).
Crawford, E. D. et al. Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations. Prostate Cancer Prostatic Dis. 22, 24–38 (2019).
Janknegt, R. A. Total androgen blockade with the use of orchiectomy and nilutamide (Anandron) or placebo as treatment of metastatic prostate cancer. Anandron International Study Group. Cancer 72, 3874–3877 (1993).
Crawford, E. D. et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N. Engl. J. Med. 321, 419–424 (1989).
Kolvenbag, G. J., Blackledge, G. R. & Gotting-Smith, K. Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development. Prostate 34, 61–72 (1998).
Prostate Cancer Trialists’ collaborative group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 355, 1491–1498 (2000).
Dagher, A. et al. Approval summary: docetaxel in combination with prednisone for the treatment of androgen-independent hormone-refractory prostate cancer. Clin. Cancer Res. 10, 8147–8151 (2004).
Caffo, O., Veccia, A., Kinspergher, S. & Maines, F. Abiraterone acetate and its use in the treatment of metastatic prostate cancer: a review. Future Oncol. 14, 431–442 (2018).
Tran, C. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324, 787–790 (2009).
Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).
Sugawara, T. et al. Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models. Int. J. Cancer 145, 1382–1394 (2019).
Rice, M. A., Malhotra, S. V. & Stoyanova, T. Second-generation antiandrogens: from discovery to standard of care in castration resistant prostate cancer. Front. Oncol. 9, 801 (2019).
Schulte, B., Morgans, A. K., Shore, N. D. & Pezaro, C. Sorting through the maze of treatment options for metastatic castration-sensitive prostate cancer. Am. Soc. Clin. Oncol. Educ. Book 40, 1–10 (2020).
Sartor, O. & de Bono, J. S. Metastatic prostate cancer. N. Engl. J. Med. 378, 645–657 (2018).
Nakazawa, M., Paller, C. & Kyprianou, N. Mechanisms of therapeutic resistance in prostate cancer. Curr. Oncol. Rep. 19, 13 (2017).
de Bono, J. et al. Olaparib for metastatic castration-resistant prostate cancer. N. Engl. J. Med. 382, 2091–2102 (2020).
Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).
Abida, W. et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis. Oncol. 2017, PO.17.00029 (2017).
Abida, W. et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 5, 471–478 (2019).
Abida, W. et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl Acad. Sci. USA 116, 11428–11436 (2019).
Ferraldeschi, R. et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur. Urol. 67, 795–802 (2015).
Mateo, J. et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J. Clin. Invest. 130, 1743–1751 (2020).
Annala, M. et al. Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 8, 444–457 (2018).
Gupta, S. et al. Whole genomic copy number alterations in circulating tumor cells from men with abiraterone or enzalutamide-resistant metastatic castration-resistant prostate cancer. Clin. Cancer Res. 23, 1346–1357 (2017).
Isaacsson Velho, P. et al. Wnt-pathway activating mutations are associated with resistance to first-line abiraterone and enzalutamide in castration-resistant prostate cancer. Eur. Urol. 77, 14–21 (2020).
Pritchard, C. C. et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375, 443–453 (2016).
Torquato, S. et al. Genetic alterations detected in cell-free DNA are associated with enzalutamide and abiraterone resistance in castration-resistant prostate cancer. JCO Precis. Oncol. 3, PO.18.00227 (2019).
Azad, A. A. et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin. Cancer Res. 21, 2315–2324 (2015).
Wyatt, A. W. et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2, 1598–1606 (2016).
Antonarakis, E. S. Current understanding of resistance to abiraterone and enzalutamide in advanced prostate cancer. Clin. Adv. Hematol. Oncol. 14, 316–319 (2016).
Li, Y. et al. Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer. Clin Cancer Res. 26, 1965–1976 (2020).
Wang, Z. et al. Significance of the TMPRSS2:ERG gene fusion in prostate cancer. Mol. Med. Rep. 16, 5450–5458 (2017).
Tucci, M. et al. Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions. Onco. Targets Ther. 11, 7353–7368 (2018).
Jernberg, E., Bergh, A. & Wikstrom, P. Clinical relevance of androgen receptor alterations in prostate cancer. Endocr. Connect. 6, R146–R161 (2017).
Crona, D. J. & Whang, Y. E. Androgen receptor-dependent and -independent mechanisms involved in prostate cancer therapy resistance. Cancers 9, 67 (2017).
Balbas, M. D. et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife 2, e00499 (2013).
Prekovic, S. et al. The effect of F877L and T878A mutations on androgen receptor response to enzalutamide. Mol. Cancer Ther. 15, 1702–1712 (2016).
Moilanen, A. M. et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci. Rep. 5, 12007 (2015).
Joseph, J. D. et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 3, 1020–1029 (2013).
Rathkopf, D. E. et al. Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide. Ann. Oncol. 28, 2264–2271 (2017).
Zhang, T., Karsh, L. I., Nissenblatt, M. J. & Canfield, S. E. Androgen receptor splice variant, AR-V7, as a biomarker of resistance to androgen axis-targeted therapies in advanced prostate cancer. Clin. Genitourin. Cancer 18, 1–10 (2020).
Uo, T., Plymate, S. R. & Sprenger, C. C. The potential of AR-V7 as a therapeutic target. Expert Opin. Ther. Targets 22, 201–216 (2018).
Antonarakis, E. S. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 371, 1028–1038 (2014).
Brown, L. C., Lu, C., Antonarakis, E. S., Luo, J. & Armstrong, A. J. Androgen receptor variant-driven prostate cancer II: advances in clinical investigation. Prostate Cancer Prostatic Dis. 23, 367–380 (2020).
Armstrong, A. J. et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: the PROPHECY study. J. Clin. Oncol. 37, 1120–1129 (2019).
Zhao, J. et al. Cross-resistance among next-generation antiandrogen drugs through the AKR1C3/AR-V7 axis in advanced prostate cancer. Mol. Cancer Ther. 19, 1708–1718 (2020).
Morsy, A. & Trippier, P. C. Reversal of apalutamide and darolutamide aldo-keto reductase 1C3-mediated resistance by a small molecule inhibitor. ACS Chem. Biol. 15, 646–650 (2020).
Palit, S. A. et al. TLE3 loss confers AR inhibitor resistance by facilitating GR-mediated human prostate cancer cell growth. eLife 8, e47430 (2019).
Arora, V. K. et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155, 1309–1322 (2013).
Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).
Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).
Bishop, J. L. et al. The master neural transcription factor BRN2 is an androgen receptor-suppressed driver of neuroendocrine differentiation in prostate cancer. Cancer Discov. 7, 54–71 (2017).
Dardenne, E. et al. N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell 30, 563–577 (2016).
Yin, Y. et al. N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway. Mol. Cancer 18, 11 (2019).
Beltran, H. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298–305 (2016).
Aggarwal, R. et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J. Clin. Oncol. 36, 2492–2503 (2018).
Ku, S. Y., Gleave, M. E. & Beltran, H. Towards precision oncology in advanced prostate cancer. Nat. Rev. Urol. 16, 645–654 (2019).
Zhang, Z. et al. Loss of CHD1 promotes heterogeneous mechanisms of resistance to AR-targeted therapy via chromatin dysregulation. Cancer Cell 37, 584–598.e11 (2020).
Ware, K. E. et al. Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer. Oncotarget 7, 50507–50521 (2016).
Miao, L. et al. Disrupting androgen receptor signaling induces snail-mediated epithelial-mesenchymal plasticity in prostate cancer. Cancer Res. 77, 3101–3112 (2017).
Song, B. et al. Targeting FOXA1-mediated repression of TGF-beta signaling suppresses castration-resistant prostate cancer progression. J. Clin. Invest. 129, 569–582 (2019).
Jividen, K. et al. Genomic analysis of DNA repair genes and androgen signaling in prostate cancer. BMC Cancer 18, 960 (2018).
Risdon, E. N., Chau, C. H., Price, D. K., Sartor, O. & Figg, W. D. PARP inhibitors and prostate cancer: to infinity and beyond BRCA. Oncologist 26, e115–e129 (2020).
Castro, E. et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 37, 490–503 (2019).
Lang, S. H. et al. A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer. Int. J. Oncol. 55, 597–616 (2019).
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines®). Prostate cancer version 2.2021. NCCN https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (2021).
Mateo, J. et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 21, 162–174 (2020).
Cheng, H. H., Pritchard, C. C., Boyd, T., Nelson, P. S. & Montgomery, B. Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur. Urol. 69, 992–995 (2016).
Zafeiriou, Z. et al. Genomic analysis of three metastatic prostate cancer patients with exceptional responses to carboplatin indicating different types of DNA repair deficiency. Eur. Urol. 75, 184–192 (2019).
Pomerantz, M. M. et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostatecancer. Cancer 123, 3532–3539 (2017).
Bilusic, M., Madan, R. A. & Gulley, J. L. Immunotherapy of prostate cancer: facts and hopes. Clin. Cancer Res. 23, 6764–6770 (2017).
Nava Rodrigues, D. et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J. Clin. Invest. 128, 4441–4453 (2018).
Marcus, L., Lemery, S. J., Keegan, P. & Pazdur, R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin. Cancer Res. 25, 3753–3758 (2019).
FDA. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors (2020).
Marabelle, A. et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 21, 1353–1365 (2020).
Schweizer, M. T. et al. CDK12-mutated prostate cancer: clinical outcomes with standard therapies and immune checkpoint blockade. JCO Precis. Oncol. 4, 382–392 (2020).
Antonarakis, E. S. et al. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-Ribose) polymerase inhibitors, and PD-1 inhibitors. JCO Precis. Oncol. 4, 370–381 (2020).
van Dessel, L. F. et al. The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact. Nat. Commun. 10, 5251 (2019).
Adelaiye-Ogala, R. et al. Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor. Mol. Cancer Ther. 19, 1436–1447 (2020).
Marques, R. B. et al. High efficacy of combination therapy using PI3K/AKT inhibitors with androgen deprivation in prostate cancer preclinical models. Eur. Urol. 67, 1177–1185 (2015).
Zhang, Y. et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol. Cancer 17, 45 (2018).
Carver, B. S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011).
Crumbaker, M., Khoja, L. & Joshua, A. M. AR signaling and the PI3K pathway in prostate cancer. Cancers 9, 34 (2017).
Murillo-Garzon, V. & Kypta, R. WNT signalling in prostate cancer. Nat. Rev. Urol. 14, 683–696 (2017).
Chen, W. S. et al. Genomic drivers of poor prognosis and enzalutamide resistance in metastatic castration-resistant prostate cancer. Eur. Urol. 76, 562–571 (2019).
Semenza, G. L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2010).
Semenza, G. L. Hypoxia-inducible factors in physiology and medicine. Cell 148, 399–408 (2012).
Schito, L. & Semenza, G. L. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2, 758–770 (2016).
Stewart, G. D. et al. The relevance of a hypoxic tumour microenvironment in prostate cancer. BJU Int. 105, 8–13 (2010).
Bharti, S. K. et al. Hypoxia patterns in primary and metastatic prostate cancer environments. Neoplasia 21, 239–246 (2019).
Mitani, T., Harada, N., Nakano, Y., Inui, H. & Yamaji, R. Coordinated action of hypoxia-inducible factor-1alpha and beta-catenin in androgen receptor signaling. J. Biol. Chem. 287, 33594–33606 (2012).
Mitani, T. et al. Hypoxia enhances transcriptional activity of androgen receptor through hypoxia-inducible factor-1alpha in a low androgen environment. J. Steroid Biochem. Mol. Biol. 123, 58–64 (2011).
Fernandez, E. V. et al. Dual targeting of the androgen receptor and hypoxia-inducible factor 1alpha pathways synergistically inhibits castration-resistant prostate cancer cells. Mol. Pharmacol. 87, 1006–1012 (2015).
Schmidt, K. T., Chau, C. H., Price, D. K. & Figg, W. D. Precision oncology medicine: the clinical relevance of patient-specific biomarkers used to optimize cancer treatment. J. Clin. Pharmacol. 56, 1484–1499 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03385655 (2021).
Bastos, D. A. & Antonarakis, E. S. Galeterone for the treatment of advanced prostate cancer: the evidence to date. Drug Des. Devel. Ther. 10, 2289–2297 (2016).
Taplin, M. E. et al. Clinical factors associated with AR-V7 detection in ARMOR3-SV, a randomized trial of galeterone (Gal) vs enzalutamide (Enz) in men with AR-V7+ metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 35, 5005–5005 (2017).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02438007 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02606123 (2018).
Le Moigne, R. et al. Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor. J. Clin. Oncol. 37, 257–257 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04421222 (2020).
Schweizer, M. T. et al. A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer. PLoS ONE 13, e0198389 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02532114 (2018).
Madan, R. A. et al. Phase 2 study of seviteronel (INO-464) in patients with metastatic castration-resistant prostate cancer after enzalutamide treatment. Clin. Genitourin. Cancer 18, 258–267 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02130700 (2018).
Yamamoto, Y. et al. Generation 2.5 antisense oligonucleotides targeting the androgen receptor and its splice variants suppress enzalutamide-resistant prostate cancer cell growth. Clin. Cancer Res. 21, 1675–1687 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03300505 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03888612 (2021).
Wang, Y., Jiang, X., Feng, F., Liu, W. & Sun, H. Degradation of proteins by PROTACs and other strategies. Acta Pharm. Sin. B 10, 207–238 (2020).
Asangani, I. A. et al. BET bromodomain inhibitors enhance efficacy and disrupt resistance to ar antagonists in the treatment of prostate cancer. Mol. Cancer Res. 14, 324–331 (2016).
Welti, J. et al. Targeting bromodomain and extra-terminal (BET) family proteins in castration-resistant prostate cancer (CRPC). Clin. Cancer Res. 24, 3149–3162 (2018).
Piha-Paul, S. A. et al. First-in-human study of mivebresib (ABBV-075), an oral pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/refractory solid tumors. Clin. Cancer Res. 25, 6309–6319 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02391480 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02711956 (2020).
Ha, H. et al. Inhibitors of prostate-specific membrane antigen in the diagnosis and therapy of metastatic prostate cancer — a review of patent literature. Expert Opin. Ther. Pat. https://doi.org/10.1080/13543776.2021.1878145 (2021).
Evans, M. J. et al. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc. Natl Acad. Sci. USA 108, 9578–9582 (2011).
Diao, W., Cao, Y., Su, D. & Jia, Z. Impact of (68) Gallium prostate-specific membrane antigen tracers on the management of patients with prostate cancer who experience biochemical recurrence. BJU Int. 127, 153–163 (2020).
Rahbar, K. et al. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A retrospective analysis of overall survival. Eur. J. Nucl. Med. Mol. Imaging 45, 12–19 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03042468 (2020).
Teply, B. A. et al. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 19, 76–86 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02090114 (2020).
Denmeade, S. R. et al. TRANSFORMER: Bipolar androgen therapy (BAT) versus enzalutamide (E) for castration-resistant metastatic prostate cancer (mCRPC). J. Clin. Oncol. 38, 5517 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02286921 (2020).
Puhr, M. et al. The glucocorticoid receptor is a key player for prostate cancer cell survival and a target for improved antiandrogen therapy. Clin. Cancer Res. 24, 927–938 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03437941 (2020).
Beltran, H. et al. A phase II trial of the aurora kinase a inhibitor alisertib for patients with castration-resistant and neuroendocrine prostate cancer: efficacy and biomarkers. Clin. Cancer Res. 25, 43–51 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01799278 (2018).
Zhang, Y. et al. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. Nat. Commun. 9, 4080 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04179864 (2020).
Liu, Q. et al. Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-beta1/STAT3 axis-regulated EMT. Cell Death Dis. 8, e3007 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02614859 (2020).
Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015).
de Bono, J. et al. Final overall survival (OS) analysis of PROfound: olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations. Ann. Oncol. 31 (Suppl. 4), 507–549 (2020).
Abida, W. et al. Preliminary results from the triton2 study of rucaparib in patients (PTS) with DNA Damage Repair (DDR)-deficient metastatic castration-resistant prostate cancer (MCRPC): updated analyses. Ann. Oncol. 30, v325–v355 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02952534 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02975934 (2020).
Sweeney, C. J. et al. IMbassador250: a phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. Cancer Res. 80 (Suppl. 16), CT014 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03016312 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04191096 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03834493 (2021).
Schmidt, K. T. et al. Measurement of NLG207 (formerly CRLX101) nanoparticle-bound and released camptothecin in human plasma. J. Pharm. Biomed. Anal. 181, 113073 (2020).
Schmidt, K. T. et al. Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors. Cancer Chemother. Pharmacol. 86, 475–486 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02769962 (2021).
Karzai, F. et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J. Immunother. Cancer 6, 141 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02484404 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03834519 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01485861 (2021).
de Bono, J. S. et al. Randomized phase II study evaluating akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN Loss. Clin. Cancer Res. 25, 928–936 (2019).
Kolinsky, M. P. et al. A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer. Ann. Oncol. 31, 619–625 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02525068 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02091531 (2019).
Graham, L. et al. A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer. Invest. N. Drugs 36, 458–467 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02407054 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02215096 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02125084 (2020).
Kelly, W. K. et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J. Clin. Oncol. 30, 1534–1540 (2012).
Petrylak, D. P. et al. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 16, 417–425 (2015).
Ning, Y. M. et al. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28, 2070–2076 (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/results/NCT01605227 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/results/NCT01522443 (2018).
Sonpavde, G. P. et al. Cabozantinib for progressive metastatic castration-resistant prostate cancer following docetaxel: combined analysis of two phase 3 trials. Eur. Urol. Oncol. 3, 540–543 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03170960 (2020).
Agarwal, N. et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results of cohort 6 of the COSMIC-021 study. J. Clin. Oncol. 38, 5564 (2020).
Schmidt, K. T. et al. Anti-tumor activity of NLG207 (formerly CRLX101) in combination with enzalutamide in preclinical prostate cancer models. Mol. Cancer Ther. https://doi.org/10.1158/1535-7163.MCT-20-0228 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03531827 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03568656 (2021).
Welti, J. et al. Targeting p300/CBP axis in lethal prostate cancer. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-20-0751 (2021).
Teo, M. Y., Rathkopf, D. E. & Kantoff, P. Treatment of advanced prostate cancer. Annu. Rev. Med. 70, 479–499 (2019).
Scher, H. I. et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J. Clin. Oncol. 34, 1402–1418 (2016).
Kapoor, A., Wu, C., Shayegan, B. & Rybak, A. P. Contemporary agents in the management of metastatic castration-resistant prostate cancer. Can. Urol. Assoc. J. 10, E414–E423 (2016).
Caffo, O. et al. Clinical outcomes of castration-resistant prostate cancer treatments administered as third or fourth line following failure of docetaxel and other second-line treatment: results of an Italian multicentre study. Eur. Urol. 68, 147–153 (2015).
de Wit, R. et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N. Engl. J. Med. 381, 2506–2518 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02485691 (2020).
Khalaf, D. J. et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 20, 1730–1739 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02125357 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04139772 (2019).
Handy, C. E. & Antonarakis, E. S. Sequencing treatment for castration-resistant prostate cancer. Curr. Treat. Options Oncol. 17, 64 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03777982 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02685397 (2020).
Morris, M. et al. Alliance A031201: a phase III trial of enzalutamide (ENZ) versus enzalutamide, abiraterone, and prednisone (ENZ/AAP) for metastatic castration resistant prostate cancer (mCRPC). J. Clin. Oncol. 37, 5008 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01949337 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02257736 (2020).
Posadas, E. M. et al. Pharmacokinetics, safety, and antitumor effect of apalutamide with abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: phase 1b study. Clin. Cancer Res. 26, 3517–3524 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00268476 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03009981 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02799602 (2021).
Smith, M. et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20, 408–419 (2019).
Den, R. B., George, D., Pieczonka, C. & McNamara, M. Ra-223 treatment for bone metastases in castrate-resistant prostate cancer: practical management issues for patient selection. Am. J. Clin. Oncol. 42, 399–406 (2019).
Knechel, M. A., Schmidt, K. T. & Figg, W. D. Combination treatment in metastatic castration-resistant prostate cancer: can we safely boost efficacy by adding radium-223? Cancer Biol. Ther. 21, 1–3 (2020).
Cursano, M. C. et al. Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: a review. Crit. Rev. Oncol. Hematol. 146, 102864 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02194842 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04237584 (2020).
Lorente, D. et al. Decline in circulating tumor cell count and treatment outcome in advanced prostate cancer. Eur. Urol. 70, 985–992 (2016).
Scher, H. I. et al. Assessment of the validity of nuclear-localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration-resistant prostate cancer. JAMA Oncol. 4, 1179–1186 (2018).
Del Re, M. et al. AR-V7 and AR-FL expression is associated with clinical outcome: a translational study in patients with castrate resistant prostate cancer. BJU Int. https://doi.org/10.1111/bju.14792 (2019).
Antonarakis, E. S. et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 1, 582–591 (2015).
Clark, E. et al. Prostate cancer androgen receptor splice variant 7 biomarker study — a multicentre randomised feasibility trial of biomarker-guided personalised treatment in patients with advanced prostate cancer (the VARIANT trial) study protocol. BMJ Open 9, e034708 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03903835 (2020).
Crippa, A. et al. The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer. Trials 21, 579 (2020).
West, J. et al. Towards multidrug adaptive therapy. Cancer Res. 80, 1578–1589 (2020).
Zhang, J., Cunningham, J. J., Brown, J. S. & Gatenby, R. A. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nat. Commun. 8, 1816 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03511196 (2020).
West, J. B. et al. Multidrug cancer therapy in metastatic castrate-resistant prostate cancer: an evolution-based strategy. Clin. Cancer Res. 25, 4413–4421 (2019).
Smith, M. R. et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N. Engl. J. Med. 378, 1408–1418 (2018).
Hussain, M. et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 378, 2465–2474 (2018).
Fizazi, K. et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 380, 1235–1246 (2019).
Davis, I. D. et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N. Engl. J. Med. 381, 121–131 (2019).
Penson, D. F. et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J. Clin. Oncol. 34, 2098–2106 (2016).
Beer, T. M. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).
Beer, T. M. et al. Enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur. Urol. 71, 151–154 (2017).
Armstrong, A. J. et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J. Clin. Oncol. 37, 2974–2986 (2019).
Small, E. J. et al. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann. Oncol. 30, 1813–1820 (2019).
Fizazi, K. et al. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). J. Clin. Oncol. 38, 514 (2020).
Sternberg, C. N. et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 382, 2197–2206 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02531516 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02446444 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03860987 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04736199 (2021).
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Urology thank M. Shiota and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
Rights and permissions
About this article
Cite this article
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
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41585-021-00438-4
This article is cited by
-
Sex differences orchestrated by androgens at single-cell resolution
Nature (2024)
-
Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance
Acta Pharmacologica Sinica (2023)
-
A potassium-chloride co-transporter promotes tumor progression and castration resistance of prostate cancer through m6A reader YTHDC1
Cell Death & Disease (2023)
-
CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation
Cell Communication and Signaling (2022)
-
Idarubicin combats abiraterone and enzalutamide resistance in prostate cells via targeting XPA protein
Cell Death & Disease (2022)