Abstract
Background
Approximately 10–30% of men with mCRPC will test positive for AR-V7 using one of two analytically and clinically validated circulating tumor cell (CTC)-based assays. These men have poor outcomes with approved AR-targeting therapies but may retain sensitivity to chemotherapy. Here, we discuss the clinical implications of testing and strategies that may benefit AR splice variant (AR-V)-positive men and discuss whether such variants are passengers or drivers of aggressive clinical behavior.
Methods
We conducted a systemic review of the literature, covering updates since our 2016 review on androgen receptor variants in mCRPC, outcomes, and existing and novel approaches to therapy. We provide an expert opinion about management strategies for AR-V7-positive men and key unanswered research questions.
Results
AR-V7-positive men, defined by Epic nuclear protein detection or the modified AdnaTest mRNA detection in CTCs, identify a subset of men with mCRPC that have a low probability of response to AR-targeting therapy with short progression-free and overall survival in multivariable analyses. AR-variants do not exist in isolation, but rather in the context of a complex, heterogeneous, and evolving mCRPC genome and phenotype as well as patient-specific clinical heterogeneity, and multiple mechanisms of resistance likely exist in patients regardless of AR-V7 detection. Efforts to develop broader resistance assays are needed, and effective treatment strategies beyond taxanes are needed to address the causal driver role of AR-variants and to benefit patients with AR-V-expressing prostate cancer.
Conclusions
CTC AR-V7 detection using the AdnaTest mRNA or Epic nuclear protein assays represents the first analytically and prospective clinically validated liquid biopsy assays that may inform treatment decisions in men with mCRPC, particularly after failure of first-line AR-therapy. The importance of AR-variants is likely to increase with the earlier use of AR-targeting strategies in other settings, and novel interventions for these men are needed.
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References
Gandhi J, Afridi A, Vatsia S, Joshi G, Joshi G, Kaplan SA, et al. The molecular biology of prostate cancer: current understanding and clinical implications. Prostate Cancer Prostatic Dis. 2018;21:22–36.
Ciccarese C, Santoni M, Brunelli M, Buti S, Modena A, Nabissi M, et al. AR-V7 and prostate cancer: the watershed for treatment selection? Cancer Treat Rev. 2016;43:27–35.
Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69:16–22.
Luo J. Development of AR-V7 as a putative treatment selection marker for metastatic castration-resistant prostate cancer. Asian J Androl. 2016;18:580–5.
Mayrhofer M, De Laere B, Whitington T, Van Oyen P, Ghysel C, Ampe J, et al. Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis. Genome Med. 2018;10:85.
Henzler C, Li Y, Yang R, McBride T, Ho Y, Sprenger C, et al. Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer. Nat Commun. 2016;7:13668.
De Laere B, Oeyen S, Mayrhofer M, Whitington T, van Dam PJ, Van Oyen P, et al. TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2019;25:1766–73.
Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, et al. Genomic hallmarks and structural variation in metastatic prostate. Cancer Cell. 2018;174:758–769.e759.
Antonarakis ES, Armstrong AJ, Dehm SM, Luo J. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostatic Dis. 2016;19:231–41.
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028–38.
Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Zhu Y, et al. Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol. 2017;35:2149–56.
Lokhandwala PM, Riel SL, Haley L, Lu C, Chen Y, Silberstein J, et al. Analytical validation of androgen receptor splice variant 7 detection in a clinical laboratory improvement amendments (CLIA) laboratory setting. J Mol Diagn. 2017;19:115–25.
Markowski MC, Silberstein JL, Eshleman JR, Eisenberger MA, Luo J, Antonarakis ES. Clinical utility of CLIA-grade AR-V7 testing in patients with metastatic castration-resistant prostate cancer. JCO Precis Oncol. 2017; 2017.
Scher HI, Lu D, Schreiber NA, Louw J, Graf RP, Vargas HA, et al. Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol. 2016;2:1441–9.
Scher HI, Graf RP, Schreiber NA, Jayaram A, Winquist E, McLaughlin B, 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. 2018;4:1179–86.
Scher HI, Graf RP, Schreiber NA, McLaughlin B, Jendrisak A, Wang Y, et al. Phenotypic heterogeneity of circulating tumor cells informs clinical decisions between AR signaling inhibitors and taxanes in metastatic prostate cancer. Cancer Res. 2017;77:5687–98.
Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, et al. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res. 2014;74:2270–82.
Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 2015;1:582–91.
Antonarakis ES, Tagawa ST, Galletti G, Worroll D, Ballman K, Vanhuyse M, et al. Randomized, noncomparative, phase II trial of early switch from docetaxel to cabazitaxel or vice versa, with integrated biomarker analysis, in men with chemotherapy-naive, metastatic, castration-resistant prostate cancer. J Clin Oncol. 2017;35:3181–8.
Tagawa ST, Antonarakis ES, Gjyrezi A, Galletti G, Kim S, Worroll D, et al. Expression of AR-V7 and ARv(567es) in circulating tumor cells correlates with outcomes to taxane therapy in men with metastatic prostate cancer treated in TAXYNERGY. Clin Cancer Res. 2019;25:1880–8.
Scher HI, Graf RP, Schreiber NA, McLaughlin B, Lu D, Louw J, et al. Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer. Eur Urol. 2017;71:874–82.
Armstrong AJ, Halabi S, Luo J, Nanus DM, Giannakakou P, Szmulewitz RZ, 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. 2019;37:1120–9.
Sharp A, Welti JC, Lambros MBK, Dolling D, Rodrigues DN, Pope L, et al. Clinical utility of circulating tumour cell androgen receptor splice variant-7 status in metastatic castration-resistant prostate cancer. Eur Urol. 2019;76:676–85.
Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, et al. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. J Clin Investig. 2019;129:192–208.
Bernemann C, Schnoeller TJ, Luedeke M, Steinestel K, Boegemann M, Schrader AJ, et al. Expression of AR-V7 in circulating tumour cells does not preclude response to next generation androgen deprivation therapy in patients with castration resistant prostate cancer. Eur Urol. 2017;71:1–3.
Steinestel J, Luedeke M, Arndt A, Schnoeller TJ, Lennerz JK, Wurm C, et al. Detecting predictive androgen receptor modifications in circulating prostate cancer cells. Oncotarget. 2019;10:4213–23.
Taplin ME, Antonarakis ES, Ferrante KJ, Horgan K, Blumenstein B, Saad F, et al. Androgen receptor modulation optimized for response-splice variant: a phase 3, randomized trial of galeterone versus enzalutamide in androgen receptor splice variant-7-expressing metastatic castration-resistant prostate cancer. Eur Urol. 2019;76:843–51.
Sobhani N, Generali D, D’Angelo A, Aieta M, Roviello G. Current status of androgen receptor-splice variant 7 inhibitor niclosamide in castrate-resistant prostate-cancer. Investig New Drugs. 2018;36:1133–7.
Schweizer MT, Haugk K, McKiernan JS, Gulati R, Cheng HH, Maes JL, et al. A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer. PLoS ONE. 2018;13:e0198389.
Yang YC, Banuelos CA, Mawji NR, Wang J, Kato M, Haile S, et al. Targeting androgen receptor activation function-1 with EPI to overcome resistance mechanisms in castration-resistant prostate cancer. Clin Cancer Res. 2016;22:4466–77.
Brand LJ, Olson ME, Ravindranathan P, Guo H, Kempema AM, Andrews TE, et al. EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer. Oncotarget. 2015;6:3811–24.
Moigne RL, Banuelos CA, Mawji NR, Tam T, Wang J, Jian K, et al. PEPI-7386 is a novel N-terminal domain androgen receptor inhibitor for the treatment of prostate cancer. European Society of Medical Oncology (ESMO) 2019 Congress; Barcelona, Spain. Ann Oncol. 2019;Abstract 503.
Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–82.
Urbanucci A, Mills IG. Bromodomain-containing proteins in prostate cancer. Mol Cell Endocrinol. 2018;462:31–40.
Hupe MC, Hoda MR, Zengerling F, Perner S, Merseburger AS, Cronauer MV. The BET-inhibitor PFI-1 diminishes AR/AR-V7 signaling in prostate cancer cells. World J Urol. 2019;37:343–9.
Asangani IA, Wilder-Romans K, Dommeti VL, Krishnamurthy PM, Apel IJ, Escara-Wilke J, et al. BET bromodomain inhibitors enhance efficacy and disrupt resistance to AR antagonists in the treatment of prostate cancer. Mol Cancer Res. 2016;14:324–31.
Faivre EJ, Wilcox D, Lin X, Hessler P, Torrent M, He W, et al. Exploitation of castration-resistant prostate cancer transcription factor dependencies by the novel BET inhibitor ABBV-075. Mol Cancer Res. 2017;15:35–44.
Doroshow DB, Eder JP, LoRusso PM. BET inhibitors: a novel epigenetic approach. Ann Oncol. 2017;28:1776–87.
Rosati R, Polin L, Ducker C, Li J, Bao X, Selvakumar D, et al. Strategy for tumor-selective disruption of androgen receptor function in the spectrum of prostate cancer. Clin Cancer Res. 2018;24:6509–22.
Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012;72:3457–62.
Weiss GJ, Jameson G, Von Hoff DD, Valsasina B, Davite C, Di Giulio C, et al. Phase I dose escalation study of NMS-1286937, an orally available polo-like kinase 1 inhibitor, in patients with advanced or metastatic solid tumors. Investig New Drugs. 2018;36:85–95.
Zhang Z, Hou X, Shao C, Li J, Cheng JX, Kuang S, et al. Plk1 inhibition enhances the efficacy of androgen signaling blockade in castration-resistant prostate cancer. Cancer Res. 2014;74:6635–47.
Einstein D, Choudhury A, Saylor P, Werner L, Croucher P, Ridinger M, et al. A phase 2 study of the combination of PLK1 inhibitor, onvansertib, with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). In: Proceedings of the 20th Asian Pacific Prostate Cancer Conference 2019; Melbourne, Australia. 2019;Abstract 1044.
Annala M, Vandekerkhove G, Khalaf D, Taavitsainen S, Beja K, Warner EW, et al. Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 2018;8:444–57.
Gonzalez-Billalabeitia E, Conteduca V, Wetterskog D, Jayaram A, Attard G. Circulating tumor DNA in advanced prostate cancer: transitioning from discovery to a clinically implemented test. Prostate Cancer Prostatic Dis. 2019;22:195–205.
De Laere B, Rajan P, Gronberg H, Dirix L, Lindberg J. Androgen receptor burden and poor response to abiraterone or enzalutamide in TP53 wild-type metastatic castration-resistant prostate cancer. JAMA Oncol. 2019;5:1060–2.
Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428–36.
de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381:2506–18.
Zhao P, Zhu Y, Cheng L, Luo J. Detection of androgen receptor (AR) and AR-V7 in small cell prostate carcinoma: Diagnostic and therapeutic implications. Asian J Urol. 2019;6:109–13.
Aggarwal R, Huang J, Alumkal JJ, Zhang L, Feng FY, Thomas GV, et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J Clin Oncol. 2018;36:2492–503.
Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408–18.
James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338–51.
Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378:2465–74.
Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352–60.
Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235–46.
Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381:121–31.
Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13–24.
Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, 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. 2019;37:2974–86.
Mohler JL, Antonarakis ES. NCCN guidelines updates: management of prostate cancer. J Natl Compr Canc Netw. 2019;17:583–6.
Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5:471–8.
Antonarakis ES. Cyclin-dependent kinase 12, immunity, and prostate cancer. N Engl J Med. 2018;379:1087–9.
Tucker MD, Zhu J, Marin D, Gupta RT, Gupta S, Berry WR, et al. Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer. Cancer Med. 2019;8:4644–55.
Chung JH, Dewal N, Sokol E, Mathew P, Whitehead R, Millis SZ, et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. JCO Precis Oncol. 2019; 3.
Antonarakis ES, Velho PI, Agarwal N, Santos VS, Maughan BL, Pili R, et al. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, PARP inhibitors, and PD1 inhibitors. European Society of Medical Oncology (ESMO) 2019 Congress; Barcelona, Spain. Ann Oncol. 2019;Abstract 845.
Boudadi K, Suzman DL, Anagnostou V, Fu W, Luber B, Wang H, et al. Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer. Oncotarget. 2018;9:28561–71.
Teply BA, Wang H, Luber B, Sullivan R, Rifkind I, Bruns 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. 2018;19:76–86.
Yamamoto Y, Loriot Y, Beraldi E, Zhang F, Wyatt AW, Al Nakouzi N, 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. 2015;21:1675–87.
Snoek R, Cheng H, Margiotti K, Wafa LA, Wong CA, Wong EC, et al. In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors. Clin Cancer Res. 2009;15:39–47.
Luo J, Attard G, Balk SP, Bevan C, Burnstein K, Cato L, et al. Role of androgen receptor variants in prostate cancer: report from the 2017 mission androgen receptor variants meeting. Eur Urol. 2018;73:715–23.
Chan SC, Li Y, Dehm SM. Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal. J Biol Chem. 2012;287:19736–49.
Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2013;73:483–9.
Acknowledgements
AJA has received funding from a Prostate Cancer Foundation and Movember Global Treatment Sciences Challenge Award and the NIH under a P30 CA014236 and 1R01CA233585 – 01 grant. ESA has received funding from the Prostate Cancer Foundation, the Patrick C. Walsh Fund, and NIH grants R01 CA185297 and P30 CA006973. JL is currently funded by a Prostate Cancer Foundation grant, NIH grant R01 CA185297, and US Department of Defense Prostate Cancer Research Program grant W81XWH-19-1-0686.
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AJA has served as a paid consultant for Astrazeneca, Merck, Dendreon, Janssen, Clovis, Bayer, and Medivation/Astellas; is on the speaker’s bureau for Bayer and Dendreon; and receives research funding to his institution from Janssen, Medivation/Astellas, Sanofi-aventis, Active Biotech, Bayer, Dendreon, Merck, Astrazeneca, Genentech/Roche, BMS, Constellation, Novartis, and Pfizer. ESA has served as a paid consultant/advisor for Janssen, Pfizer, Sanofi, Dendreon, Essa, Merck, Bristol-Myers Squibb, AstraZeneca, Clovis, Eli Lilly and Amgen; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Merck, Bristol-Myers Squibb, AstraZeneca and Constellation; and is a co-inventor of an AR-V7 biomarker technology that has been licensed to Qiagen. JL has served as a paid consultant/advisor for Sun Pharma, Janssen, Tolero, and Sanofi; has received research funding to his institution from Orion, Mirati, Astellas, Sanofi, Constellation, Calibr, Pandomedx, and Gilead; and is a co-inventor of a technology that has been licensed to Tokai, Qiagen, and A&G. CL is a co-inventor of a technology that has been licensed to Tokai and Qiagen.
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Brown, L.C., Lu, C., Antonarakis, E.S. et al. Androgen receptor variant-driven prostate cancer II: advances in clinical investigation. Prostate Cancer Prostatic Dis 23, 367–380 (2020). https://doi.org/10.1038/s41391-020-0215-5
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DOI: https://doi.org/10.1038/s41391-020-0215-5
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