E U R O P E A N U R O L O GY 7 5 ( 2 019 ) 3 6 8 – 37 3 available at www.sciencedirect.com journal homepage: www.europeanurology.com Brief Correspondence Plasma Androgen Receptor and Docetaxel for Metastatic Castration-resistant Prostate Cancer Vincenza Conteduca a,b,y,*, Anuradha Jayaram b,c,d,y, Nuria Romero-Laorden e,f,y, Daniel Wetterskog b,d, Samanta Salvi a, Giorgia Gurioli a, Emanuela Scarpi a, Elena Castro e,g, Mercedes Marin-Aguilera h, Cristian Lolli a, Giuseppe Schepisi a, Antonio Maugeri a, Anna Wingate b,d, Alberto Farolfi a, Valentina Casadio a, Ana Medina i, Javier Puente j, Ma José Méndez Vidal k, Rafael Morales-Barrera l, Jose C. Villa-Guzmán m, Susana Hernando n, Alejo Rodriguez-Vida o, Aránzazu González-del-Alba p, Begoña Mellado h, Enrique Gonzalez-Billalabeitia q,r, David Olmos e,s,z, Gerhardt Attard b,c,d,z,*, Ugo De Giorgi a,z a Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; b Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK; c The Royal Marsden NHS Foundation Trust, London, UK; d University College London Cancer Institute, London, UK; e Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain; f Hospital Universitario La Princesa, Madrid, Spain; g Hospital Universitario Quirón, Madrid, Spain; h Department of Medical Oncology, IDIBAPS, Hospital Clínico y Provincial, Barcelona, Spain; i Centro Oncológico de Galicia, A Coruña, Spain; j Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), CIBERONC, k Madrid, Spain; Hospital Reina Sofía, Córdoba, Spain; l Vall d’Hebron Institute of Oncology, Vall d’ Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain; m Hospital General Universitario de Ciudad Real, Ciudad Real, Spain; n Fundación Hospital Alcorcón, Alcorcón, Spain; o Hospital p q del Mar, Barcelona, Spain; Hospital Universitario Son Espases, Palma de Mallorca, Spain; Department of Hematology & Medical Oncology, Hospital Universitario Morales Meseguer, IMIB-Universidad de Murcia, Murcia, Spain; r Universidad Católica San Antonio de Murcia-UCAM, Murcia, Spain; s CNIO- IBIMA Genitourinary Cancer Research Unit, Hospitales Universitario, virgen de la Victoria y regional de Málaga, Spain Article info Abstract Article history: Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate Accepted September 27, 2018 cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate Associate Editor: whether docetaxel is active regardless of plasma AR and to perform an exploratory Matthew Cooperberg analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain Statistical Editor: reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) Andrew Vickers response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR] = 1.61, 95% confidence interval [CI] = 1.08–2.39, p = 0.018), but not PFS (HR = 1.04, 95% CI 0.74–1.46, p = 0.8) or PSA response (odds ratio = 1.14, 95% CI = 0.65–1.99, p = 0.7). We investigated the interaction between plasma AR and treat- ment type after incorporating updated data from our prior study of 73 chemotherapy- y These authors contributed equally. z These authors jointly supervised this work as co-senior authors. * Corresponding authors. University College London Cancer Institute, Paul OGorman Building, 72 Huntley Street, London, UK. Tel. +44-2087224413 (G. Attard); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via Piero Maroncelli 40, Meldola, 47014, Italy. Tel. +39- 0543739100 (V. Conteduca). E-mail addresses: vincenza.conteduca@irst.emr.it (V. Conteduca), g.attard@ucl.ac.uk (G. Attard). https://doi.org/10.1016/j.eururo.2018.09.049 0302-2838/© 2018 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). E U RO P E A N U R O L O GY 7 5 ( 2 019 ) 3 6 8 – 37 3 369 naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line doce- Keywords: taxel patients. In an exploratory analysis of mCRPC patients receiving first-line thera- Castration-resistant prostate pies, a significant interaction was observed between plasma AR and docetaxel versus cancer abiraterone/enzalutamide for OS (HR = 0.16, 95% CI = 0.06–0.46, p < 0.001) and PFS (HR = 0.31, 95% CI = 0.12–0.80, p = 0.02). Specifically, we reported a significant difference Androgen receptor for OS favoring abiraterone/enzalutamide for AR-normal patients (HR = 1.93, 95% Plasma DNA CI = 1.19–3.12, p = 0.008) and a suggestion favoring docetaxel for AR-gained patients Docetaxel (HR = 0.53, 95% CI = 0.24–1.16, p = 0.11). These data suggest that AR-normal patients Androgen receptor–directed the- should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. rapies This treatment selection merits prospective evaluation in a randomized trial. Patient summary: We investigated whether plasma androgen receptor (AR) predicted Biomarker outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker. © 2018 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/). There are currently several approved life-prolonging patients (median 8, interquartile range 6–10). The median therapies for the treatment of metastatic castration- follow-up period of alive patients was 24 mo. As 98% of the resistant prostate cancer (mCRPC), including androgen deaths were prostate cancer related, only overall survival receptor (AR)-directed drugs and taxanes. Plasma DNA (OS), and not cancer-specific survival, was analyzed. The analysis from mCRPC patients has suggested potential median OS was 14 mo (95% confidence interval [CI] 12–23) clinical applicability with an association between plasma AR for AR-gained patients and 22 mo (95% CI 20–29) for AR- aberrations and worse outcome with AR-directed drugs [1– normal patients. Median progression-free survival (PFS) 5]. To date, detection of AR splice variants has been shown was 7 mo (95% CI 5–8) in AR-gained patients and 7 mo (95% to have potential utility for the selection of taxane versus CI 6–8) in AR-normal patients. OS was significantly shorter AR-targeted therapy for patients with mCRPC [6,7]. Howev- in AR-gained versus AR-normal patients (hazard ratio [HR] er, the relevance of plasma AR status in the context of = 1.61, 95% CI 1.08–2.39, p = 0.02), but no significant taxanes is unknown. difference was observed for PFS (HR = 1.04, 95% CI 0.74– We here aimed to evaluate the association of plasma AR 1.46,p = 0.8) or prostate-specific antigen (PSA) decline 50% status with outcomes in mCRPC patients treated with (odds ratio = 1.14, 95% CI 0.65–1.99, p = 0.7; Fig. 1B–D). docetaxel. Additionally, we aimed to perform an explorato- Next, we selected the 115 patients treated with docetaxel ry analysis to compare the difference in outcome by plasma as first-line therapy and in an exploratory, analysis AR status for patients treated either with first-line docetaxel compared them with 73 previously described patients or AR-directed therapy. treated with first-line abiraterone/enzalutamide (Fig. 1A) Plasma samples were collected, with the primary aim of [5]. A comparison of clinicopathological characteristics biomarker evaluation, from mCRPC patients, treated with between patients receiving either docetaxel or abiraterone/ standard-dose intravenous docetaxel 75 mg/m2 every 3 wk enzalutamide as first-line therapy showed significant with prednisone 5 mg twice daily for a maximum of differences in age, site of metastases, PSA, lactate dehydro- 10 cycles for mCRPC [8], between May 2011 and January genase (LDH), hemoglobin, alkaline phosphatase, and 2017 in 20 institutions. For the exploratory analysis, we plasma AR status (Supplementary Table 1). When compar- included data on patients from our previous publication [5] ing AR-normal with AR-gained patients in each treatment who received abiraterone/enzalutamide prior to chemo- group, serum LDH and PSA were significantly higher in AR- therapy at the development of mCRPC, with updated clinical gained patients treated with abiraterone/enzalutamide and follow-up with a cut-off date of December 2017. All patients serum alkaline phosphatase was significantly higher in provided signed consent to an institutional review board- plasma AR-gained patients treated with docetaxel (Supple- approved protocol before sample collection. Selection mentary Table 2). criteria, procedures, and the AR copy number (CN) droplet The interaction of docetaxel or abiraterone/enzaluta- digital polymerase chain reaction assay are described in the mide therapy and AR status was investigated using a Supplementary material. multivariable Cox proportional hazard model, which We set out to determine AR status in plasma collected showed a significant treatment interaction with AR status from 166 docetaxel-treated mCRPC patients prior to first- or for both OS (HR = 0.16, 95% CI 0.06–0.46, p < 0.001) and PFS second-line mCRPC therapy (Fig. 1A), but we had sample (HR = 0.31, 95% CI 0.12–0.80, p = 0.02; Supplementary failure in three cases. We detected plasma AR gain in Table 3). The median follow-up period for alive patients 50 patients (31%; 28% AR gain prior to first-line and 37% of the abiraterone/enzalutamide cohort was 32 mo. prior to second-line therapy). The median number of The estimated median OS and PFS as a function of docetaxel cycles was the same in AR-normal and AR-gained treatment and AR CN status are depicted in Figures 2A and 370 E U R O P E A N U RO L O GY 7 5 ( 2 019 ) 3 6 8 – 37 3 [(Fig._1)TD$IG] Fig. 1 – Study design and association of plasma AR status with clinical outcome in castration-resistant prostate cancer patients treated with docetaxel. (A) Flow chart showing the selection of docetaxel-treated patients for the primary and exploratory analyses. (B) Overall survival and (C) progression- free survival in docetaxel-treated patients. (D) Waterfall plots depicting prostate-specific antigen (PSA) declines (%) by AR copy number normal and gain in docetaxel-treated patients. Bars clipped at maximum 100%. AR = androgen receptor; CN = copy number; CRPC = castration-resistant prostate cancer; doce = docetaxel; OS = overall survival; PFS = progression-free survival. 2B, respectively. The HRs for OS (Fig. 2C) and PFS (Fig. 2D) shown to be clinically relevant [5], we observed that plasma estimated from the Cox proportional hazard regression AR gain was independently associated with worse OS analyses suggested that AR-normal patients treated with (HR = 6.55, 95% CI 2.74–15.68, p < 0.001) and PFS abiraterone/enzalutamide had a significantly lower risk of (HR = 3.24, 95% CI 1.47–7.14, p = 0.004; Supplementary death (HR = 1.93, 95% CI 1.19–3.12, p = 0.008) and progres- Table 3). sive disease (HR = 2.60, 95% CI 1.75–3.86, p < 0.001) when Metastatic CRPC patients can be treated with docetaxel compared with those treated with docetaxel, and in AR- or AR-targeting therapies as first-line therapy. We and gained patients there was a suggestion toward a lower risk others have reported that detection of circulating AR of death (HR = 0.53, 95% CI 0.24–1.16, p = 0.11; Fig. 2C) and aberrations is associated with worse outcome on abirater- progressive disease (HR = 0.82, 95% CI 0.40–1.69, p = 0.6; one/enzalutamide [2–5]. In this study, we report that Fig. 2D) with docetaxel compared with abiraterone/ plasma AR gain in docetaxel-treated patients was associated enzalutamide therapy. In multivariable analysis of first-line with significantly shorter OS. This emphasizes the urgent treatment patients, including treatment type, plasma AR clinical need of alternative treatments for AR-gained status, and other pretreatment baseline features previously patients [9]. Retrospective studies have suggested that E U RO P E A N U R O L O GY 7 5 ( 2 019 ) 3 6 8 – 37 3 371 [(Fig._2)TD$IG] Fig. 2 – Association of plasma AR status with clinical outcome in castration-resistant prostate cancer patients treated with either docetaxel or AR- directed therapies (abiraterone or enzalutamide) as first-line treatment. Interaction between AR status and treatment type, after including data from abiraterone- or enzalutamide-treated patients for (A) OS and (B) PFS. (C) Forest plot shows the hazard ratio and 95% confidence interval for (C) OS and (D) PFS in AR-normal and AR-gained patients. Abi = abiraterone, AR = androgen receptor; doce = docetaxel; enza = enzalutamide; OS = overall survival; PFS = progression-free survival. AR-V7 expression in mCRPC men can be considered a patient selection, given the different toxicity profiles of treatment-specific biomarker associated with superior taxanes compared with AR-targeting drugs. Additionally, survival for taxane therapy compared with AR therapies detection of an AR-gained clone may be more likely at [6,7]. Here, we explored whether plasma AR gain status is higher circulating tumor fraction that in itself is prognostic; associated with resistance to taxanes in an abiraterone/ this could bias the ability to ascertain the predictive value of enzalutamide-naïve population and, to avoid the influence plasma AR with AR-targeting drugs but would not change of possible cross-resistance events on the interpretation of the interpretation of the absence of difference in our survival data, we compared it with the effect seen in taxane- treatment-naive taxane-treated cohort. Lastly, we only naïve abiraterone/enzalutamide-treated patients [10]. The considered AR gain, but other concurrently assessed AR absence of a difference in outcome by AR status in aberrations (somatic point mutations or splice variants) treatment-naïve docetaxel-treated patients introduces the could provide additional or overlapping information. Our hypothesis that AR-gained patients would derive greater findings suggest that AR gain detected in plasma is benefit from treatment with taxanes in preference to associated with resistance to abiraterone/enzalutamide abiraterone/enzalutamide. However, we recognize some but not with taxanes when used in the first-line setting. limitations of our study, including the significantly different In conclusion, prospective randomized trials are warranted durations of median follow-up of alive patients between the to validate the utility of plasma AR status for treatment docetaxel and the abiraterone/enzalutamide cohort (24 vs selection in mCRPC patients. 32 mo, with overall follow-up of 24 mo); the relatively modest sample size of the cohorts, especially of AR-gained Author contributions: Gerhardt Attard had full access to all the data in patients treated with abiraterone/enzalutamide (n = 10); the study and takes responsibility for the integrity of the data and the and the retrospective, nonrandomized design. The majority accuracy of the data analysis. of patients were treated with taxanes in centers when abiraterone or enzalutamide were not widely available prior Study concept and design: Conteduca, Jayaram, Wetterskog, Castro, to chemotherapy. Nonetheless, there could be a bias due to Gonzalez-Billalabeitia, Olmos, Attard, De Giorgi. 372 E U R O P E A N U RO L O GY 7 5 ( 2 019 ) 3 6 8 – 37 3 Acquisition of data: Conteduca, Jayaram, Romero-Laorden, Wetterskog, honoraria and/or travel support from Sanofi Aventis, Astellas Medivation, Salvi, Gurioli, Castro, Wingate, Casadio, Gonzalez-Billalabeitia, Olmos, Janssen-Cilag, Bayer, BMS, Pfizer, Novartis, MSD and Roche. A. Medina Attard, De Giorgi. has received honoraria and/or travel support from BMS, Janssen-Cilag, Analysis and interpretation of data: Conteduca, Jayaram, Romero-Laorden, Bayer healthcare, Sanofi Aventis, Astellas Medivation, Roche, Novartis Wetterskog, Castro, Gonzalez-Billalabeitia, Olmos, Attard, De Giorgi. and Pfizer. D. Olmos has a compensated advisory role for Astellas, Astra- Drafting of the manuscript: Conteduca, Wetterskog, Attard. Zeneca, Bayer, Clovis, Genetech/Roche, Janssen, and[6_TD$IF] uncompensated Critical revision of the manuscript for important intellectual content: All advisory role for BioOncotech, Tokai; has received a speaker fee from authors. Astellas, Bayer, Janssen, Sanofi[7_TD$IF], and travel support from Astellas, Bayer, Statistical analysis: Scarpi. Janssen, Roche; has received research funding (to the institution): Astra- Obtaining funding: Gonzalez-Billalabeitia, Olmos, Attard, De Giorgi. Zeneca, BioOncotech, Bayer, Janssen. No potential conflicts of interest Administrative, technical, or material support: Maugeri. were disclosed by the other authors. Supervision: Attard. Other: Provided patients—Conteduca, Jayaram, Romero-Laorden, Castro, Funding/Support and role of the sponsor: V. Conteduca was funded by a Marin-Aguilera, Lolli, Schepisi, Farolfi, Maugeri, Medina, Puente, Vidal, European Society of Medical Oncology Translational Clinical Research Morales-Barrera, Villa-Guzmán, Hernando, Rodriguez-Vida, González- Fellowship. A. Jayaram is supported by a grant from the Medical Research del-Alba, Mellado, Gonzalez-Billalabeitia, Olmos, Attard, De Giorgi. Council (MR/P002072/1). G. Attard is supported by a Cancer Research UK Advanced Clinician Scientist Grant (A22744). This work was funded in Financial disclosures: Gerhardt Attard certifies that all conflicts of part by Prostate Cancer UK (PG12-49), the “Instituto de Salud Carlos III” interest, including specific financial interests and relationships and (ISCII) PI16/01565 grant[8_TD$IF]. E.[9_TD$IF] Gonzalez-Billalabeitia was funded by a grant affiliations relevant to the subject matter or materials discussed in the from the “Instituto de Salud Carlos III” (ISCIII) PI15/01499. N. Romero- manuscript (eg, employment/affiliation, grants or funding, consultan- Laorden was funded by a grant from the “Instituto de Salud Carlos III” cies, honoraria, stock ownership or options, expert testimony, royalties, (CM14-00200). E. Castro is supported by a Prostate Cancer Foundation or patents filed, received, or pending), are the following: G. Attard Young Investigator Award (2017). E. Castro and D. Olmos are supported reports receiving commercial research grants from Janssen, Arno by grants from the Ministerio de Economía, Industria y Competitividad Therapeutics, and Innocrin Pharma; has received honoraria and/or (JCI-2014-19129 to E.C., RYC-2015-18625 to D.O[10_TD$IF].). B. Mellado and M.[1_TD$IF] travel support from the speakers’ bureaus of Janssen, Astellas, Sanofi- Marin-Aguilera work were supported by the Instituto de Salud Carlos III- Aventis, and Roche/Ventana; has received travel support from Pfizer, Subdirección General de Evaluación y Fomento de la Investigación (PI12/ Abbott Laboratories, Bayer Healthcare, and Essa Pharmaceuticals; has 01226 and PI15/676)[12_TD$IF] and co-funded by the European Regional ownership interest (including patents) in The Institute of Cancer Development Fund. Funding from CERCA Programme/Generalitat de Research Rewards to Inventors; and is a consultant for/advisory board Catalunya is gratefully acknowledged. During the conduct of the study, E. member of Janssen-Cilag, Veridex, Bayer Healthcare, Roche/Ventana, Castro was supported by a grant from the Ministerio de Educación, Astellas, Medivation, Pfizer, Novartis, Millennium Pharma, Abbott Cultura y Deportes (CAS17/00182). The funders of the study had no role Laboratories, and Essa Pharma. V. Conteduca, E. Gonzalez-Billalabeitia[1_TD$IF], in study design, data collection, data analysis, data interpretation, or and U. De Giorgi received speaker honoraria or travel support from writing of the report. The corresponding authors had full access to all Astellas, Janssen-Cilag, and Sanofi-Aventis. V. Conteduca received data and had the final responsibility for the decision to submit for consulting fee from Bayer. D. Olmos received research funding from publication. Janssen and Bayer. J[2_TD$IF] Puente reports receiving commercial research grants from Pfizer and Astellas; has received honoraria and/or travel support Acknowledgments: We thank the participating men and their families from the speakers’ bureaus of Pfizer, Astellas, Janssen, MSD, Roche, who suffered from metastatic prostate cancer and nonetheless gave the Bristol, AstraZeneca, Boehringer, Pierre Fabre, Kyowa, Celgene, Lilly, gift of participation so that others might benefit. Merck, Ipsen and Eisai; and is a consultant for Pfizer, Astellas, Janssen, MSD, Bayer, Roche, Bristol, AstraZeneca, Boehringer, Novartis, Clovis, Ipsen, EssaPharma[3_TD$IF], Eisai and Sanofi. B. Mellado reports receiving Appendix A. Supplementary data commercial research grants from Roche and Bayer; has received travel support from Pfizer and Janssen; and is a consultant for/advisory board Supplementary data associated with this article can be member of Roche, Sanofi, Janssen, Astellas Oncology, Pfizer, Novartis, found, in the online version, at https://doi.org/10.1016/j. Bristol-Myers Squibb and Ipsen. M. Marín-Aguilera has received travel eururo.2018.09.049. support from Bristol-Myers Squibb. A. Rodriguez-Vida reports receiving commercial research grants from Takeda, MSD and Pfizer; has received honoraria and/or travel support from the speakers’ bureaus of Janssen, References Astellas, Sanofi-Aventis, Bayer, BMS and Roche. N. Romero Laorden has received honoraria and/or travel support from Bayer, Astellas, Janssen- [1] Annala M, Vandekerkhove G, Khalaf D, et al. Circulating tumor DNA Cilag, and Sanofi-Aventis. M.J. Mendez Vidal has received honoraria and genomics correlate with resistance to abiraterone and enzaluta- /or travel support from Janssen-Cilag, Bayer Healthcare, Sanofi Aventis, mide in prostate cancer. Cancer Discov 2018;8:444–57. Astellas Medivation, Roche, Novartis and Pfizer. R Morales-Barrera has [2] Romanel A, Tandefelt DG, Conteduca V, et al. Plasma AR and received honoraria and/or travel support from Bayer, Roche, Astellas, abiraterone-resistant prostate cancer. Sci Transl Med 2015;312, Janssen-Cilag, MSD and Sanofi-Aventis. A. González del Alba has received 312re10. honoraria and/or travel support from Sanofi Aventis, Astellas Medivation, [3] Salvi S, Casadio V, Conteduca V, et al. Circulating cell-free AR and Janssen-Cilag, Bayer, BMS, Pfizer, Novartis, MSD, Roche,[4_TD$IF] EUSA Pharma CYP17A1 copy number variations may associate with outcome of and Eisai[5_TD$IF]. E. Castro reports receiving commercial research grants from metastatic castration-resistant prostate cancer patients treated Astra Zeneca, Bayer, Janssen; has received honoraria and/or travel with abiraterone. Br J Cancer 2015;112:1717–24. support from the speakers’ bureaus of Astra Zeneca, Astellas, Bayer, [4] Salvi S, Casadio V, Conteduca V, et al. Circulating AR copy number Janssen, Pfizer, Bristol-Myers and Roche; and is an advisory board and outcome to enzalutamide in docetaxel-treated metastatic cas- member of Astellas, Bayer and Janssen. S. Hernando Polo has received tration-resistant prostate cancer. Oncotarget 2016;7:37839–45. E U RO P E A N U R O L O GY 7 5 ( 2 019 ) 3 6 8 – 37 3 373 [5] Conteduca V, Wetterskog D, Sharabiani MTA, et al. Androgen receptor [8] Tannock IF, de Wit R, Berry WR, et al. TAX 327 Investigators. gene status in plasma DNA associates with worse outcome on enzalu- Docetaxel plus prednisone or mitoxantrone plus prednisone for tamide or abiraterone for castration-resistant prostate cancer: a multi- advanced prostate cancer. N Engl J Med 2004;351:1502–12. institution correlative biomarker study. Ann Oncol 2017;28:1508–16. [9] van Soest RJ. Liquid biopsies and plasma DNA: paving the way for [6] Antonarakis ES, Lu C, Luber B, et al. Androgen receptor splice variant personalized medicine in metastatic castration-resistant prostate 7 and efficacy of taxane chemotherapy in patients with metastatic cancer. Ann Oncol 2017;28:1408–9. castration-resistant prostate cancer. JAMA Oncol 2015;1:582–91. [10] van Soest RJ, de Morrée ES, Kweldam CF, et al. Targeting the [7] Scher HI, Graf RP, Schreiber NA, et al. Nuclear-specific AR-V7 protein androgen receptor confers in vivo cross-resistance between enza- localization is necessary to guide treatment selection in metastatic lutamide and docetaxel, but not cabazitaxel, in castration-resistant castration-resistant prostate cancer. Eur Urol 2017;71:874–82. prostate cancer. Eur Urol 2015;67:981–5.