Androgen Receptor-targeted Agents Research Articles

Sequencing strategies in the new treatment landscape of prostate cancer.

Over the last 10 years, a number of new agents approved for the treatment of metastatic castration-resistant prostate cancer have led to a significant improvement in overall survival. The addition of new agents to androgen deprivation therapy has also allowed a paradigmatic change in the treatment of metastatic hormone-sensitive prostate cancer by improving overall survival in comparison with androgen deprivation therapy alone. Furthermore, recent data concerning the efficacy of three different androgen receptor-targeting agents in patients with nonmetastatic castration-resistant prostate cancer have opened up new scenarios for future patients' management. Defining the best sequencing strategies for men with prostate cancer is a currently unmet medical need, and choosing treatment is often challenging for clinicians because of the lack of direct comparisons of the available agents. The aim of this paper is to provide a comprehensive review of the literature concerning current sequencing strategies for prostate cancer patients.

Advances in targeted alpha therapy for prostate cancer.

Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.

An exploratory retrospective multicenter study of prognostic factors in mCRPC patients undergoing enzalutamide treatment: Focus on early PSA decline and kinetics at time of progression.

Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor-targeting agents in metastatic castration-resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed the early PSA response to enzalutamide (ENZ) by measuring the PSA doubling time (PSADT) and PSA velocity (PSAV) while monitoring oncologic outcomes and survival in Japanese patients. We analyzed a total of 241 patients with mCRPC who were treated with ENZ. The patients' median age was 75 ± 7.9 years (range, 53-93 years). There were 171 (71%) predocetaxel cases, and 70 (29%) post docetaxel cases. PSA-progression-free survival (PFS) and overall survival (OS) were assessed according to Prostate Cancer Working Group 2 criteria. This study was approved by the Institutional Review Board of Gunma University Hospital (No. 1595). We observed 77 good response (GR; case in which PSA remained low after treatment) cases (31.9%), 125 acquired resistance (AR; decline in PSA after treatment followed by progression) cases (51.9%), and 39 primary resistance (PR; lack of decline in PSA) cases (16.2%). Predocetaxel, PSA-PFS, and OS were significantly higher compared with post docetaxel (PSA-PFS: 47.0 vs 13.4 weeks, P < .001; OS: not yet reached vs 80.7 weeks, P < .001). Multivariate analysis of prognostic factors, including PSA response at 4 weeks, was performed using Cox regression analysis. ECOG PS (0 vs 1-2), hemoglobin (Hb; ≥ 12.2 vs < 12.2 g/dL), time to CRPC ( ≥ 12 vs < 12 m), docetaxel treatment history (no vs yes), and a PSA reduction of 50% at 4 weeks were significant predictors of OS (all, P < .05). In cases of AR (n = 125), multivariate analysis showed that PSA kinetic factors, such as PSADT and PSAV (ng/mL/m), Hb, time to CRPC, PSADT ( ≥ 2 vs < 2 m), and PSAV ( < 20 vs ≥ 20 ng/mL/m), were all predictive of OS following PSA-progression (P < .05). Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostic factor for mCRPC patients.

Flutamide as an Alternative Anti-androgen Agent and Predictor of the Efficacy of Novel Androgen Receptor-targeted Agents.

There are few reports that verify the relationship between the therapeutic effects of flutamide and novel androgen receptor-targeted agents. We aimed to evaluate the benefits of flutamide as an alternative anti-androgen agent and its effects on the efficacy of novel androgen receptor-targeted agents. Patients with castration-resistant prostate cancer on novel androgen receptor-targeted agents without prior docetaxel therapy were included. Changes in prostate-specific antigen (PSA) level were recorded. Patients who responded well to flutamide (Flutamide effective) following initial maximum androgen blockade (MAB) showed significantly higher changes in serum PSA levels (p=0.039) and PSA-progression-free survival (PFS) rate (p=0.016) following enzalutamide therapy compared to those who did not respond well to flutamide. Multivariate analysis showed that the factor of Flutamide effective was significantly associated with a good PSA-PFS rate following enzalutamide therapy (HR=7.36, 95%CI=1.4-38.71, p=0.018). Patients showing good response to flutamide following initial MAB may achieve a satisfactory PSA-PFS rate with subsequent enzalutamide therapy.

Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer.

Genomic studies of localized and metastatic prostate cancer have identified a high prevalence of clinically actionable alterations including mutations in DNA repair genes. In this manuscript, we review the current knowledge on DNA repair defects in prostate cancer and provide an overview of how these alterations can be targeted towards a personalized prostate cancer management. Twenty to 25% of metastatic prostate cancers harbor defects in DNA repair genes, most commonly in the homologous recombination genes. These defects confer increased sensitivity to platinum chemotherapy or poly (ADP-ribose) polymerase (PARP) inhibitors. Recent trials also support a synergistic effect of combining these therapies with androgen receptor-targeting agents. Identification of mismatch-repair defects could result in defining a prostate cancer population who may benefit from immune checkpoint inhibitors. These data have implications for family testing and early diagnosis, as many of these mutations are linked to inherited risk of prostate cancer. The DNA damage repair pathways are clinically relevant in prostate cancer, being a target for precision medicine; combination with standard-of-care androgen receptor (AR)-targeting agents may be synergistic.

Real-world outcomes in patients with metastatic castration-resistant prostate cancer receiving second-line chemotherapy versus an alternative androgen receptor-targeted agent (ARTA) following early progression on a first-line ARTA in a US community oncology setting

ObjectiveThis retrospective observational study assessed if second-line chemotherapy vs. androgen receptor-targeted agents (ARTAs; abiraterone/enzalutamide) is associated with improved outcomes in metastatic castration-resistant prostate cancer (mCRCaP) patients who experience early progression on first-line ARTAs in a US community setting. MethodsPatients with mCRCaP (n = 345) who progressed ≤ 12 months after first-line ARTA and received second-line chemotherapy (docetaxel/cabazitaxel; n = 147) or ARTA (n = 198) between May 2011 and October 2014 were identified. Overall survival (OS), prostate-specific antigen (PSA) response and progression, and clinical response were compared for second-line chemotherapy vs. ARTA, using one-sided tests from second-line therapy initiation. Multivariate analyses were adjusted for: year, age, metastases, opioid use, Eastern Cooperative Oncology Group performance score, PSA, hemoglobin, alkaline phosphatase, lactate dehydrogenase (LDH), and albumin levels. ResultsPatients receiving second-line chemotherapy vs. ARTA were younger (median: 74 vs. 79 years) and had a poorer prognosis in terms of PSA, LDH, alkaline phosphatase, albumin and hemoglobin levels, opioid use, and Halabi risk score (P < 0.05). Response rates were higher for chemotherapy vs. ARTA (PSA: adjusted odds ratio = 2.27, P = 0.005; clinical: adjusted odds ratio = 1.78; P = 0.020) and time to PSA progression was longer (adjusted hazard ratio [aHR] = 0.66; P = 0.010). A trend favored chemotherapy vs. ARTA for OS (aHR = 0.81, P = 0.148). Among patients with poor prognostic features, those receiving chemotherapy had significantly improved OS (Halabi intermediate-/high-risk score: aHR = 0.55, P = 0.009; hemoglobin < 11 g/dl: aHR = 0.41, P = 0.002; LDH > upper limit of normal: aHR = 0.18, P = 0.014; albumin < lower limit of normal: aHR = 0.42, P = 0.020). ConclusionFollowing early progression on first-line ARTA, second-line chemotherapy may be more beneficial in mCRCaP compared with second-line ARTA in patients with a poor prognosis.

Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel, Cabazitaxel, and Androgen Receptor-Targeted Agents.

Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor-targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC). Records of 574 consecutive patients treated (2012-2016) at 44 centers in 6 countries were retrospectively examined. A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P= .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate-specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA. OS appeared to increase with the number of life-extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit.

AR-V7 Androgen Receptor Variant as a Predictor of Response to Androgen-receptor Targeting Agents Used to Treat Castration-refractory Metastatic Prostate Cancer

Several systemic treatment options are currently available for patients with metastatic castration-refractory prostate cancer (mCRPC), including the androgen-receptor targeting agents (ARTA) enzalutamide and abiraterone, the taxanes docetaxel and cabazitaxel, and the radioisotope drug 223-radium dichloride. In some patients with mCRCP, alternative splicing of androgen receptor (AR) mRNA occurs, resulting in the formation of a truncated AR lacking the androgen-binding domain. These receptors activate downstream signalling pathways even without the ligand. Recent studies show that the presence of the AR-V7 (ARV - AR variants) splicing variant is associated with resistance to ARTA. Bec>ause the presence of AR-V7 does not affect the efficacy of other systemic therapies used in mCRCPs, particularly taxanes, AR-V7 is a candidate predictive biomarker for the individualisation of mCRCP treatment. Two types of assays based on mRNA or abnormal protein detection are used to detect AR-V7 in circulating tumour cells. To describe the current status of AR-V7 testing in mCRPC and possible applications of this method for predicting outcomes of ARTA therapy. The percentage of CTC AR-V7+ in ARTA-naive men is relatively low at baseline, but in patients pretreated with ARTA, the prevalence of AR-V7 increases to 19-34%. Given the relatively high expected prevalence, AR-V7 testing may be economically feasible in this population. The proportion of AR-V7+ patients responding to ARTA retreatment appears to be very low, at only 4.8%. AR-V7 testing could thus be useful if an ARTA switch is considered in a patient progressing onto an ARTA drug. Both protein-based tests and mRNA-based tests are currently undergoing clinical validation in prospective studies, with results expected within a year.Key words: prostate cancer - abiraterone - enzalutamide - alternative splicing - drug resistanceSubmitted: 30. 8. 2017Accepted: 5. 11. 2017 doc. MUDr. Tomáš Büchler, Ph.D. received honorary lectures and publications from Astellas and Janssen and a travel grant from Janssen. Supported by Ministry of Health, Czech Republic - conceptual development of research organization Thomayer Hospital - TN 0064190. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

The treatment of metastatic prostate cancer

Prostate cancer is the second most common cancer in men worldwide. The incidence of prostate cancer is increasing with an ageing population. Since the introduction of prostate-specific antigen testing in Western countries, prostate cancers are now being diagnosed earlier. The treatment of metastatic prostate cancer has progressed dramatically in the past decade and includes advances in chemotherapy, androgen receptor-targeted agents, immunotherapy, radiopharmaceuticals and bone-targeted agents. These new treatments bring a new range of side effects, which must be managed promptly and effectively. An understanding of potential treatment toxicities and their management is essential for nursing staff in order to provide a high standard of care for men with prostate cancer.

Sequencing in metastatic castration-resistant prostate cancer (mCRPC): Updated results of the FLAC International Database.

267 Background: Optimal sequencing of new androgen-receptor targeted agents (ART) abiraterone and enzalutamide with docetaxel (DOC) and cabazitaxel (CABA) is unknown. In this large retrospective cohort of mCRPC patients (pts) treated with CABA after docetaxel (DOC), we evaluated the impact of 3 different sequences: DOC → CABA (group 1, n = 267) Or DOC → ART → CABA (group 2, n = 183) Or DOC → CABA → ART (group 3, n = 124). Methods: Records of 574 consecutive mCRPC patients were retrospectively collected in 44 centres in 6 European countries (France, Spain, UK, Greece, Poland, Turkey) from August 2012 to July 2016. Disease history and clinical characteristics at initiation of DOC therapy and outcomes were collected. Factors influencing OS were evaluated using multivariate stepwise logistic regression. Results: At DOC initiation, median age was 67 years, 83% of pts were ECOG 0-1, 45.1% had pain and 10.8% had visceral metastases. Median number of DOC cycles was 7 (6 in group 2, 7 in groups 1 and 3). Median number of CABA cycles was 6 (6 in groups 1 and 2, 7 in group 3). Median duration of ART treatment was 5.9 and 4.4 mths in groups 2 and 3, retrospectively. Median OS from first DOC cycle were 30.1, 37.1 and 40.1 mths in groups 1, 2 and 3, respectively. Factors influencing OS are summarized in the table below. Conclusions: Results of this retrospective cohort suggest that patients receiving DOC → CAB → ART show the greatest OS. High baseline PSA, short response to first-ADT and clinical progression of pts are major prognostic factors of OS at DOC initiation. The window of opportunity for chemotherapy should not be missed. [Table: see text]

Real-world outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving second-line (2L) chemotherapy (CT) vs alternative androgen receptor-targeted agents (ARTA) after lack of response to first-line (1L) ARTA in US community oncology practices.

214 Background: The relationship between treatment sequence and mCRPC outcomes is unclear. This retrospective study assessed if 2L CT vs alternative ARTA is associated with improved outcomes in pts with lack of response to 1L ARTA in the US community oncology setting. Methods: Using Altos electronic medical records, we identified 345 mCRPC pts with lack of response to 1L ARTA (abiraterone or enzalutamide) who received 2L docetaxel or cabazitaxel (CT cohort N = 147), or alternative ARTA (ARTA cohort N = 198) from May 2011 to Oct 2014. Outcomes were evaluated from start of 2L therapy and compared for 2L CT vs ARTA cohorts using one-sided tests. Prostate-specific antigen (PSA) response ( ≥ 50% reduction) and overall survival (OS) were assessed using logistic and Cox proportional hazard regression models adjusted for year, age, metastases, opioid use, ECOG performance score, PSA, hemoglobin (Hb), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and albumin (Alb) levels. Results: At start of 2L therapy, pts receiving CT vs ARTA were younger (median age, 74 vs 79 yr) and had a worse prognosis: higher mean PSA (439 vs 231 ng/mL), LDH (344 vs 234 U/L) and ALP (241 vs 166 U/L), lower mean Hb (11 vs 12 g/dL), higher mean Halabi risk score (159 vs 137; JCO 2014:32;671–7), increased opioid use (42 vs 22%), and more pts had Alb &lt; lower limit of normal (LLN; 25 vs 15%); all p &lt; 0.01. More pts in the CT vs ARTA cohort had a PSA response (adjusted odds ratio = 2.27, p = 0.005) and there was a non-statistically significant trend toward improved OS for 2L CT vs ARTA (adjusted hazard ratio [aHR] = 0.81, p = 0.148). Among pts with poor prognostic features, those in the CT cohort had significantly improved OS (Halabi intermediate–high risk score: aHR = 0.55 p = 0.009; Hb &lt; 11 g/dL: aHR = 0.41 p = 0.002; LDH &gt; upper limit of normal: aHR = 0.18 p = 0.014; Alb &lt; LLN: aHR = 0.42 p = 0.020), compared with those in the ARTA cohort. Conclusions: Treatment with 2L CT, vs 2L ARTA, may be more suitable for pts with a lack of response to 1L ARTA, particularly in pts with a poor prognosis. Funding: Sanofi Genzyme.

Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone-sensitive prostate cancer.

Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone-sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer-related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone-sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration-resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone-sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone-sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone-sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor-targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone-sensitive prostate cancer, and discusses future perspectives in this field.

Taxane Chemotherapy for Hormone-Naïve Prostate Cancer with Its Expanding Role as Breakthrough Strategy.

Historically, androgen-deprivation therapy (ADT) was the only primary treatment for metastatic prostate cancer. After prostate cancer develops into castration-resistant prostate cancer (CRPC), there are a few life-prolonging drugs, including taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, which have been proved in clinical trials. However, the prognosis of men with CRPC is still poor. The duration from initiation of ADT to CRPC has not improved in recent decades because no novel therapeutic options have emerged. However, recently, up-front docetaxel chemotherapy has been shown to prolong progression-free as well as overall survival in men with metastatic hormone-naïve prostate cancer. This offers a new way to expand the role of chemotherapy for hormone-naïve prostate cancer. In this review, we summarize the proof-of-concept as well as the current status of taxane chemotherapy for hormone-naïve prostate cancer, focusing on phase 3 clinical trials investigating oncological outcome, and discuss the future direction in this field.

Sequencing current therapies in the treatment of metastatic prostate cancer.

The standard treatment for metastatic prostate cancer is androgen deprivation therapy. However, progressive, metastatic disease usually develops, giving rise to metastatic castration-resistant prostate cancer (mCRPC). Great improvements have been made recently in the management of mCRPC, with current approved treatments including chemotherapy, androgen receptor-targeted agents, immunotherapies and radiopharmaceuticals. While the emergence of multiple effective therapies is encouraging, devising a treatment strategy can be difficult and it is becoming increasingly important, and challenging, to identify factors that influence the ideal timing of specific therapies. Considering where to place these agents in the treatment schedule of mCRPC, or whether these agents should be sequenced or combined to derive the optimal benefit for the patient, is not yet clear. Furthermore, cross-resistance may exist between these agents, which may ultimately influence treatment decisions and sequence choices. Preliminary data are emerging regarding the safety and activity for sequential treatment regimens, but there are currently no prospective studies. As prostate cancer is highly heterogeneous clinically, it is likely that no single treatment sequence will be optimal for all patients. However, at present, there are no validated biomarkers to guide individualized treatment for mCRPC. Here we review available data for the different mCRPC treatments, discussing potential sequencing of agents and possible cross-resistance or synergy among the recently approved and emerging therapies.

Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer

IntroductionTreatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of cabazitaxel, abiraterone and enzalutamide. With new systemic therapies available, the optimal treatment sequence of these drugs in mCRPC becomes increasingly important. As shown recently, patients who had previously been treated with abiraterone showed impaired responses to docetaxel, suggesting clinical cross-resistance [1]. In the present study, we aimed to identify cross-resistance between taxanes (docetaxel and cabazitaxel) and the new hormonal agents abiraterone and enzalutamide. As a potential mechanism for cross-resistance, we investigated the effects on androgen receptor (AR) nuclear translocation of these compounds. MethodsTo identify cross-resistance, we determined the effects of docetaxel, cabazitaxel, abiraterone and enzalutamide on cell viability in prostate cancer cell lines with acquired resistance to abiraterone and enzalutamide. Time-lapse confocal microscopy was used to study the dynamics of AR nuclear translocation. ResultsWe observed impaired efficacy of docetaxel, cabazitaxel and enzalutamide in the abiraterone-resistant cell line, compared to the non-resistant cell line, providing evidence for in vitro cross-resistance. Impaired efficacy of docetaxel, cabazitaxel and abiraterone was observed in the enzalutamide-resistant cell line. Furthermore, docetaxel and cabazitaxel inhibited AR nuclear translocation, which was also observed for abiraterone and enzalutamide. ConclusionsIn conclusion we found substantial preclinical evidence for cross-resistance between the taxanes docetaxel and cabazitaxel, and AR targeting agents abiraterone and enzalutamide. Since these compounds all interfere with AR-signalling, this strongly suggests a common mechanism of action, and thus a potential mechanism for cross-resistance in mCRPC.

Toward Development of Targeted Nonsteroidal Antiandrogen-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid−Gadolinium Complex for Prostate Cancer Diagnostics

Androgen receptors are present in most advanced prostate cancer specimens, having a critical role in development of this type of cancer. For correct prognosis of patient conditions and treatment monitoring, noninvasive imaging techniques have great advantages over surgical procedures. We developed synthetic methodologies for preparation of novel androgen receptor-targeting agents in an attempt to build a versatile platform for prostate cancer imaging and treatment. The structure of these compounds comprises of a lanthanoid metal ion, gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA)-based binding fragment and, connected to it by a flexible linker, bicalutamide-derived nonsteroidal antiandrogen moiety. A representative gadolinium complex 15 was evaluated as a magnetic resonance imaging (MRI) agent in C57/bl6 male mouse bearing orthotopic TRAMP C2 prostate tumor.

Arylisothiocyanato selective androgen receptor modulators (SARMs) for prostate cancer

A new series of androgen receptor targeted agents (ARTA) was prepared and tested in androgen-dependent and -independent prostate cancer cell lines. These agents were bicalutamide analogs with isothiocyanato substituted B-rings. Also, the linker sulfone of R-bicalutamide was maintained or replaced with several alternative linkages including ether, amine, N-methylamine, thioether, and methylene (in this case the product was a racemic mixture) functional groups at the X-position. To expand the structure–activity relationship (SAR) of these arylisothiocyanato AR ligands, B-ring halogenated arylisothiocyanato ligands were also prepared and tested. The arylisothiocyanato AR ligands showed strong binding affinities to AR ranging from 0.6 to 54nM. Among them, thioether and ether linkages demonstrated high binding affinities (0.6 and 4.6nM, respectively) and selective cell growth inhibition (approximately 3- to 6-fold) for LNCaP, an androgen-dependent prostate cancer cell line, when compared to the androgen independent prostate cell lines (DU145, PC-3, and PPC-1) and a bladder cell line (TSU-Pr1). However, the ligands were inactive (IC50>100mM) in a normal monkey kidney cell line (CV-1) that was used as the control for non-specific toxicity.