Androgen Synthesis Inhibitors Research Articles

Consequences of Different Corticosteroids on Serum Potassium and Prostate-Specific Antigen in Patients Receiving Abiraterone for Castration-Resistant Prostate Cancer: A Retrospective Observational Study.

Background:Abiraterone acetate is an androgen synthesis inhibitor approved for the treatment of castration-resistant prostate cancer (CRPC). Although co-administration of either prednisone or prednisolone at 10 mg/d has been recommended to reduce the risk of abiraterone-induced hyperaldosteronism (notably hypokalemia) and to give adjunctive pain relief effects, whether these glucocorticoids can be substituted by dexamethasone remains unknown.Methods:We performed a retrospective review of medical records of patients who were given abiraterone for the treatment of CRPC with either prednisolone (ABI/PSL) 10 mg/d or dexamethasone (ABI/DEX) 0.5 or 1 mg/d between 2014 and 2017 in Juntendo University Nerima Hospital. Demographic and biochemical data including prostate-specific antigen (PSA) level were retrieved from the electronic medical records.Results:Fifty-three eligible patients (27 in ABI/PSL group and 26 in ABI/DEX group) were extracted from the records. Both groups showed no significant changes in serum potassium level before and after starting treatment. In the ABI/PSL group, 12 patients (46%) showed elevations of PSA and 7 patients (27%) discontinued treatment within 3 months. In contrast, in the ABI/DEX group, only 6 patients (25%) showed elevations of PSA and 3 patients (13%, all were given dexamethasone 1 mg/d) discontinued treatment.Conclusions:Dexamethasone and prednisolone may be equally effective in preventing abiraterone-induced hypokalemia.

Targeting Binding Function-3 of the Androgen Receptor Blocks Its Co-Chaperone Interactions, Nuclear Translocation, and Activation.

The development of new antiandrogens, such as enzalutamide, or androgen synthesis inhibitors like abiraterone has improved patient outcomes in the treatment of advanced prostate cancer. However, due to the development of drug resistance and tumor cell survival, a majority of these patients progress to the refractory state of castration-resistant prostate cancer (CRPC). Thus, newer therapeutic agents and a better understanding of their mode of action are needed for treating these CRPC patients. We demonstrated previously that targeting the Binding Function 3 (BF3) pocket of the androgen receptor (AR) has great potential for treating patients with CRPC. Here, we explore the functional activity of this site by using an advanced BF3-specific small molecule (VPC-13566) that was previously reported to effectively inhibit AR transcriptional activity and to displace the BAG1L peptide from the BF3 pocket. We show that VPC-13566 inhibits the growth of various prostate cancer cell lines, including an enzalutamide-resistant cell line, and reduces the growth of AR-dependent prostate cancer xenograft tumors in mice. Importantly, we have used this AR-BF3 binder as a chemical probe and identified a co-chaperone, small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA), as an important AR-BF3 interacting partner. Furthermore, we used this AR-BF3-directed small molecule to demonstrate that inhibition of AR activity through the BF3 functionality can block translocation of the receptor into the nucleus. These findings suggest that targeting the BF3 site has potential clinical importance, especially in the treatment of CRPC and provide novel insights on the functional role of the BF3 pocket. Mol Cancer Ther; 15(12); 2936-45. ©2016 AACR.

Targeting the androgenic pathway in elderly patients with castration-resistant prostate cancer: A meta-analysis of randomized trials.

The novel hormonal drugs have recently entered in the armamentarium of therapies for treatment of metastatic castration-resistant prostate cancer (CRPC). First reports are available for their use in elderly men with CRPC. A meta-analysis of randomized controlled trials (RCTs) has been performed. PubMed, the Cochrane Library, and American Society of Clinical Oncology (ASCO) University Meeting were searched for data on the use of new hormonal treatment in elderly patients with CRPC. Nine studies for a total of 3512 elderly patients were available for meta-analysis. Six studies reported outcomes of patients aged >75 years old while 2 studies reported on patients aged >70 years old. The pooled analysis of the androgen synthesis inhibitors revealed significantly increased overall survival (OS) due to antiandrogen agents compared with placebo or placebo and prednisone (hazard ratio (HR) for death: HR = 0.74, 95% CI: 0.67-0.82; P < 0.00001). Moreover, the new antiandrogenic therapy significantly improved the progression-free survival (HR = 0.45, 95% CI: 0.31-0.65; P < 0.0001). The incidence of any grade ≥3 adverse effect was only moderately higher during with the antiandrogenic therapy as compared to the control arms (response rate = 1.03, 95% CI: 0.88-1.20; P = 0.72). This study confirmed that agents targeting the androgen axis (i.e., enzalutamide, abiraterone) significantly prolonged OS in elderly men with CRPC.

Effects of sex hormone-binding globulin (SHBG) on androgen bioactivity in vitro

Biochemical assessments of androgen status (hyper- or hypoandrogenism) are usually based on serum testosterone concentrations. According to the free hormone hypothesis, sex hormone-binding globulin (SHBG) determines free and bioavailable testosterone concentrations. Previous studies have suggested that in vitro androgen bioassay results may also be influenced by SHBG and correlate with free or bioavailable testosterone concentrations. To test this hypothesis, we established a stable HEK293 cell line with high expression of the human androgen receptor (AR) and a luciferase reporter downstream of a classical androgen response element. Importantly, we demonstrate that bioassay results are sensitive to dilution effects which increase apparent bioactivity in an SHBG-dependent manner. We therefore adopted a method using undiluted serum, which reduced cell proliferation but did not significantly affect the luciferase signal, cell viability or cytotoxicity. To correct for serum matrix effects, we applied signal correction based on internal controls with AR agonists or antagonists. Using this method, we provide direct evidence that in vitro androgen bioactivity reflects the inhibitory effects of SHBG, and correlates with free or bioavailable testosterone concentrations in adult hypogonadal men receiving androgen replacement therapy. In men receiving anti-androgens, serum bioactivity decreased tenfold while serum testosterone concentrations decreased only four-fold. Further pilot results in prostate cancer patients showed that androgen synthesis inhibitors result in more complete inhibition of androgen bioactivity than gonadorelin-based androgen deprivation therapy, even in patients whose testosterone concentrations were undetectable by mass spectrometry. We conclude that in vitro androgen reporter bioassays are useful tools to study how androgen bioactivity in serum is determined by androgens, anti-androgens as well as SHBG, provided that dilution and matrix effects are accounted for.

Development and Implementation of a High-Throughput High-Content Screening Assay to Identify Inhibitors of Androgen Receptor Nuclear Localization in Castration-Resistant Prostate Cancer Cells.

Patients with castration-resistant prostate cancer (CRPC) can be treated with abiraterone, a potent inhibitor of androgen synthesis, or enzalutamide, a second-generation androgen receptor (AR) antagonist, both targeting AR signaling. However, most patients relapse after several months of therapy and a majority of patients with relapsed CRPC tumors express the AR target gene prostate-specific antigen (PSA), suggesting that AR signaling is reactivated and can be targeted again to inhibit the relapsed tumors. Novel small molecules capable of inhibiting AR function may lead to urgently needed therapies for patients resistant to abiraterone, enzalutamide, and/or other previously approved antiandrogen therapies. Here, we describe a high-throughput high-content screening (HCS) campaign to identify small-molecule inhibitors of AR nuclear localization in the C4-2 CRPC cell line stably transfected with GFP-AR-GFP (2GFP-AR). The implementation of this HCS assay to screen a National Institutes of Health library of 219,055 compounds led to the discovery of 3 small molecules capable of inhibiting AR nuclear localization and function in C4-2 cells, demonstrating the feasibility of using this cell-based phenotypic assay to identify small molecules targeting the subcellular localization of AR. Furthermore, the three hit compounds provide opportunities to develop novel AR drugs with potential for therapeutic intervention in CRPC patients who have relapsed after treatment with antiandrogens, such as abiraterone and/or enzalutamide.

Cytochrome P450 17A1 Inhibitor Abiraterone Acetate Counteracts the Heat Shock Protein 27's Cell Survival Properties in Prostate Cancer Cells

Introduction: Inhibition of androgen synthesis by abiraterone acetate (AA) entails enhanced overall survival rates and clinical benefit for patients with locally advanced and metastasized prostate cancer (PC). The expression of heat shock protein 27 (HSP27) is generally associated with cytoprotection and was demonstrated to mediate chemoresistance under cytostatic therapy, for instance, docetaxel treatment. In this study, we investigated the impact of AA treatment on HSP27 expression and PC cell growth. Materials and Methods: HSP27 expression levels in docetaxel and AA-treated PC cell lines LNCaP and PC-3 were determined by SDS PAGE and Western blot analysis. Proliferation assays were performed using a CASY Cell Counter and Analyzer Model TT (Roche Applied Science). Results: Despite significantly increased HSP27 expression in PC cells incubated with docetaxel, Western blot analysis implicated a significant reduction of the cytoprotective HSP27 in AA-treated PC cells. Notably, HSP27 stably overexpressed in PC-3-HSP27 cells did not appear as an HSP27-mediated proliferation benefit in the presence of AA as shown in docetaxel incubation studies. Conclusion: In contrast to repeatedly demonstrated HSP27-driven chemoresistance related to chemotherapeutics, our results may constitute a broader molecular mode of action of AA chemotherapy. AA efficacy may exert an HSP27 suppressive role that goes beyond the primarily assumed inhibition of androgen biosynthesis.

A single-center experience with abiraterone as treatment for metastatic castration-resistant prostate cancer

BackgroundContinuous stimulation of the androgen receptor (AR) axis is a prerequisite for growth in castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) is a potent inhibitor of extracellular and intracellular androgen synthesis by inhibition of the CYP-17 enzyme system, which has been shown to be up-regulated in CRPC. AA was recently introduced in the management of patients with metastatic CRPC (mCRPC) both before and after taxane-based chemotherapy. The purpose of this study is to report the initial clinical experience obtained from mCRPC patients managed on AA at Rigshospitalet, Denmark, and compare the results with phase III trial outcomes. Material and methodsSingle-centre, retrospective study including consecutive patients managed on AA for more than 2-year period. Treatment consisted of 1,000mg AA and 5mg prednisone twice daily. Outcomes of interest were prostate-specific antigen (PSA) response, clinical and radiological progression, and overall survival. ResultsA total of 73 consecutive patients with mCRPC undergoing treatment with AA between November 2012 and October 2014 were included. Median follow-up was 9.9 (0.9–23.4) months. PSA decline>50% was found in 39% of the patients. Time to biochemical and radiological progression was 3.5 and 4.9 months, respectively. Overall survival was 13.2 months (95% CI: 9.0–17.4). ConclusionOur initial experience with AA in the routine management of patients with mCRPC demonstrates an efficacy-effectiveness gap compared with clinical trial. Except for PSA response (>50% decline) in patients managed with AA, postchemotherapy results were inferior to phase III studies. This is most likely because of patient selection, which is a typical weakness when transferring results from phase III trials into clinical practice.

Abstract P5-14-04: A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer: Interim analysis

Abstract Background: The frequency of AR expression varies in the different breast cancer subtypes with 88%, 59%, and 32% expression reported in ER+, HER2+, and triple negative tumors, respectively. AR expression is associated with resistance to endocrine therapy in ER+ breast cancer. Androgen levels frequently increase following treatment with aromatase inhibitors suggesting a role for androgen synthesis inhibitors in ER+ breast cancer. AR signaling and expression are seen in triple negative breast cancer (TNBC), and a distinct AR TNBC subtype can be identified by gene expression profiling. AR expression in TNBC offers a potential therapeutic target. Preclinical and clinical studies demonstrated anti-androgen agent activity in breast cancer cell lines; preliminary clinical data suggests activity in TNBC. Orteronel is a novel, oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis that is being evaluated as endocrine therapy in various hormone-sensitive cancers. In this phase 2 study we are evaluating single agent orteronel in AR+ MBC. Methods: Pts with AR expressing MBC (≥10% staining by central immunohistochemistry) were eligible. Pts were grouped into 2 cohorts for analysis: Cohort 1-TNBC and Cohort 2-ER+ (HER2 could be +/- in this cohort). Pts must have been previously treated with standard therapy for MBC (1-3 chemotherapy regimens for TNBC, 1-3 hormonal therapies + 1 chemotherapy for ER+ patients, ≥2 HER2-targeted regimens for HER2+ patients). A 6 pt lead-in for safety and tolerability of orteronel in AR+ female MBC pts was followed by open enrollment to either cohort. All pts received 300 mg orteronel PO BID over a 4 week cycle and underwent response assessment every 2 cycles. Treatment was continued until disease progression or unacceptable toxicity. The hypothesized response rate for Cohort 1 was 10% and 13% for Cohort 2. We present the results of a protocol-specified interim analysis of the ER+ MBC pts (Cohort 2). Results: From 3/2014 to 4/2015, a total of 29 pts were enrolled on cohort 2. Median age was 65 years (range, 39-79); 90% ECOG ≤1; 90% HER2-/10% HER2+; median of 7 prior therapies (range 3-11). 93% had prior chemotherapy. Pts received a median of 2 cycles of orteronel treatment (range 1-4) and 3 pts (10%) are still on treatment. Of the 26 pts (90%) pts that have discontinued, 19 (66%) discontinued due to disease progression, 4 (14%) due to pt decision, 2 (7%) due to adverse event (AE), and 1 (3%) due to non-compliance. The most common treatment-related G 3/4 AEs were increased lipase [3 pts (10%)] and hypertension [2 pts (7%)]. There were no treatment-related SAEs or deaths on study. Three pts (10%) had stable disease as their best response. Further response evaluation is underway. Conclusions: Orteronel monotherapy was well tolerated but appears to have limited single-agent activity in this heavily pre-treated ER+ MBC pt population. The full results from this interim analysis will be presented. Citation Format: Yardley DA, Peacock N, Young RR, Silber A, Chung G, Webb CD, Jones SF, Shastry M, Midha R, DeBusk LM, Hainsworth JD, Burris HA. A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer: Interim analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-04.

Trends in utilization of novel oral therapeutic agents for men with metastatic castrate-resistant prostate cancer within the United States Veteran’s Affairs Health System.

220 Background: Therapeutic options for men with metastatic castrate resistant prostate cancer (mCRPC) have expanded significantly over the past 5 years with several new agents demonstrating improved survival, including two oral agents. Abiraterone acetate (AA), a CYP-17 androgen synthesis inhibitor, obtained initial FDA approval in 2011 for post-docetaxel (D) use, and gained expanded approval in 2012 for pre-D use. Enzalutamide (ENZ), an androgen receptor signaling inhibitor, also gained FDA approval in 2012 (post-D) and indication was expanded in 2014 (pre-D). Due to the relatively recent approvals of these agents, there is limited data on rates of uptake and prescribing patterns for patients (pts) with mCRPC. Methods: For this observational study, Veterans Affairs (VA) healthcare system data (including hospitalizations, outpatient visits, and pharmacy) were used to identify male veterans who received treatment for mCRPC between fiscal years 2008 and 2014. Descriptive statistics were used to classify treatment patterns. Results: During the time period, 75,199 pts with prostate cancer were medically or surgically castrated. Of those, 43,805 were treated with anti-androgens and 7,890 went on to receive advanced lines of therapy associated with mCRPC. The median age at the time of mCRPC treatment was 73y. Between 2008-2010 (pre-AA) and 2011-2014 (post-AA), the proportion of mCRPC pts treated with ketoconazole or D dropped from 95% to 59% (p &lt; 0.0001). Conversely, the proportion of pts who received AA or ENZ increased from 19% to 68% (p &lt; 0.0001). Among the 3,763 pts treated with AA or ENZ between 2011 and 2014, the proportion treated with first-line D decreased, while the proportion treated with first-line AA increased (p &lt; 0.00001). Conclusions: The FDA approval of AA and ENZ has had a significant impact on treatment patterns for men with mCRPC within VA, with decreased use of ketoconazole and delayed use of chemotherapy. Further information regarding patient and disease characteristics is needed. The rapid uptake of these novel agents has significant implications for disease-related outcomes as well as anticipated pharmacy costs within the VA.

Amiloride effects on abiraterone antiproliferative activity in prostate cancer cells in vitro and on clinical management of abiraterone induced mineralocorticoid excess syndrome.

175 Background: Abiraterone acetate (AA) deeply inhibits androgen synthesis but leads to an ACTH driven increase in mineralocorticoid hormones requiring glucocorticoid supplementation that may impair its antineoplastic efficacy. New strategies for the management of the AA induced mineral corticoid excess syndrome (MCES) are warranted. Methods: We analyzed in vitro the interaction in terms of proliferative activity of AA plus/minus prednisone with the steroid aldosterone receptor antagonists: eplerenone, spironolactone, a non-steroidal aldosterone receptor antagonist (PF-03882845) and the epithelial sodium channel antagonist amiloride. LNCaP were grown in a medium with charcoal-treated serum and concentration-response curves for each studied drug were performed. Besides, the activity of amiloride plus hydrochlorothiazide was assessed in the clinical management of AA induced MCES in 5 consecutive patients with castrate resistant prostate cancer. The recovery of AA induced MCES symptoms and signs was the primary end point. Results: Prednisone, spironolactone and eplerenone induced an increase in the LNCAP proliferation rate and antagonized the AA-induced reduction of the cell proliferation in a concentration-dependent manner, while PF-03882845 did not. Amiloride at high concentrations induced cell death. When combined with AA +/- prednisone, amiloride at low concentration did not interfere with AA anti-proliferative activity however an additive inhibitory effect was observed at higher concentrations. The association of amiloride with hydrochlorothiazide led to a complete disappearance of all clinical and biochemical signs of abiraterone induced MCES in the 5 treated patients. Conclusions: Amiloride and PF-03882845 do not negatively interfere with the AA inhibition of proliferative activity of prostate cancer cells in vitro. The association of amiloride plus hydrochlorothiazide is efficacious in the management AA induced MCES.

Moving Beyond the Androgen Receptor (AR): Targeting AR-Interacting Proteins to Treat Prostate Cancer.

Medical or surgical castration serves as the backbone of systemic therapy for advanced and metastatic prostate cancer, taking advantage of the importance of androgen signaling in this disease. Unfortunately, resistance to castration emerges almost universally. Despite the development and approval of new and more potent androgen synthesis inhibitors and androgen receptor (AR) antagonists, prostate cancers continue to develop resistance to these therapeutics, while often maintaining their dependence on the AR signaling axis. This highlights the need for innovative therapeutic approaches that aim to continue disrupting AR downstream signaling but are orthogonal to directly targeting the AR itself. In this review, we discuss the preclinical research that has been done, as well as clinical trials for prostate cancer, on inhibiting several important families of AR-interacting proteins, including chaperones (such as heat shock protein 90 (HSP90) and FKBP52), pioneer factors (including forkhead box protein A1 (FOXA1) and GATA-2), and AR transcriptional coregulators such as the p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2, SRC-3, as well as lysine deacetylases (KDACs) and lysine acetyltransferases (KATs). Researching the effect of-and developing new therapeutic agents that target-the AR signaling axis is critical to advancing our understanding of prostate cancer biology, to continue to improve treatments for prostate cancer and for overcoming castration resistance.

Berberine inhibits androgen synthesis by interaction with aldo-keto reductase 1C3 in 22Rv1 prostate cancer cells.

Aldo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-resistant prostate cancer by reducing androgen synthesis through the inhibition of Aldo-keto reductase family 1 member C3. Cell viability and cellular testosterone content were measured in prostate cancer cells. Aldo-keto reductase family 1 member C3 mRNA and protein level were detected by RT-PCR and Western bolt analyses, respectively. Computer analysis with AutoDock Tools explored the molecular interaction of berberine with Aldo-keto reductase family 1 member C3. We found that berberine inhibited 22Rv1 cells proliferation and decreased cellular testosterone formation in a dose-dependent manner. Berberine inhibited Aldo-keto reductase family 1 member C3 enzyme activity, rather than influenced mRNA and protein expressions. Molecular docking study demonstrated that berberine could enter the active center of Aldo-keto reductase family 1 member C3 and form π-π interaction with the amino-acid residue Phe306 and Phe311. In conclusion, the structural interaction of berberine with Aldo-keto reductase family 1 member C3 is attributed to the suppression of Aldo-keto reductase family 1 member C3 enzyme activity and the inhibition of 22Rv1 prostate cancer cell growth by decreasing the intracellular androgen synthesis. Our result provides the experimental basis for the design, research, and development of AKR1C3 inhibitors using berberine as the lead compound.

Androgen-glucocorticoid interactions in the era of novel prostate cancer therapy.

Great strides have been made in the treatment of castration-resistant prostate cancer (CRPC) with the development of new antiandrogens (enzalutamide) and more potent androgen synthesis inhibitors (abiraterone) that have both improved patient outcomes. These new drugs have also helped unravel the complex biology of androgen-androgen receptor driven prostate cancer and brought into prominence various mechanisms triggering the development of drug resistance and tumour cell survival despite use of androgen deprivation therapy (ADT). The complex role of glucocorticoids in the treatment, management and progression of patients with CRPC is integral to these advances. Historically, glucocorticoid treatment has resulted in both subjective and objective responses in patients with advanced-stage prostate cancer. With the use of these new therapeutic agents, however, unexpected glucocorticoid-related mechanisms that can cause iatrogenic stimulation of prostate cancer growth have emerged, which might contribute to drug resistance and disease progression despite optimal ADT. For example, the upregulation of glucocorticoid receptors (GRs) during enzalutamide therapy results in glucocorticoid-GR-mediated regulation of androgen target genes, leading to escape from enzalutamide blockade. Thus, understanding the biological role of glucocorticoids in patients with prostate cancer is of major importance in the era of new and evolving antiandrogen therapies.

Efficacy and safety of second-line agents for treatment of metastatic castration-resistant prostate cancer progressing after docetaxel. A systematic review and meta-analysis.

We performed a systematic review of the literature to assess the efficacy and the safety of second-line agents targeting metastatic castration-resistant prostate cancer (mCRPC) that has progressed after docetaxel. Pooled-analysis was also performed, to assess the effectiveness of agents targeting the androgen axis via identical mechanisms of action (abiraterone acetate, orteronel). We included phase III randomized controlled trials that enrolled patients with mCRPC progressing during or after first-line docetaxel treatment. Trials were identified by electronic database searching. The primary outcome of the review was overall survival. Secondary outcomes were radiographic progression-free survival (rPFS) and severe adverse effects (grade 3 or higher). Ten articles met the inclusion criteria for the review. These articles reported the results of five clinical trials, enrolling in total 5047 patients. The experimental interventions tested in these studies were enzalutamide, ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control cohorts (active drug-treated or placebo-treated), the significant overall survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001), 4.6 months for abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P < 0.0001) and 2.4 months for cabazitaxel (hazard ratio for death vs. mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001). Pooled analysis of androgen synthesis inhibitors orteronel and abiraterone resulted in significantly increased overall and progression-free survival for anti-androgen agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87, P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77, P < 0.00001). Androgen synthesis inhibitors induced significant increases in risk ratios for adverse effects linked to elevated mineralocorticoid secretion, compared to placebo (risk ratio for hypokalemia: 5.75, 95% CI 2.08 to 15.90; P = 0.0008; risk-ratio for hypertension: 2.29, 95% CI 1.02 to 5.17; P = 0.05). In docetaxel-pretreated patients enzalutamide, abiraterone-prednisone and cabazitaxel-prednisone can improve overall survival of patients, compared to placebo or to best of care at the time of study (mitoxantrone-prednisone). Agents targeting the androgen axis (enzalutamide, abiraterone, orteronel) significantly prolonged rPFS, compared to placebo. Further investigation is warranted to evaluate the benefit of combination or sequential administration of these agents. Large-scale studies are also necessary to evaluate the impact of relevant toxic effects observed in a limited number of patients (e.g., enzalutamide-induced seizures, orteronel-induced pancreatitis, and others).

Abstract OT2-1-07: A phase II study with orteronel as monotherapy in patients with androgen receptor (AR) expressing metastatic breast cancer (MBC)

Abstract Background: Androgen Receptor (AR) signaling is a new target present in and under evaluation in all breast cancer subtypes. AR expression is noted in 70%-90% of primary breast tumors, up to 75% of all breast cancer metastases and is associated with resistance to endocrine therapy. Orteronel, an oral, selective, nonsteroidal inhibitor of androgen synthesis, is being developed as an endocrine therapy for hormone-sensitive cancers. In preclinical studies, orteronel suppresses sex hormone levels in blood and hormone-dependent malignant tissue. This study will evaluate the safety and efficacy of orteronel in the treatment of AR+ MBC. Study Objectives: This phase II trial is designed to determine the response rate and disease control rate (CR+PR+SD at 6 mo) following treatment with orteronel in pts with AR+ MBC. Two groups will be evaluated: Cohort 1 will include pts with AR+, triple negative (TN) (ER-/PR-/HER2-) MBC, and Cohort 2 will include pts with AR+, ER+ and/or PR+ MBC (may be HER2+ or HER2-). Secondary objectives include evaluation of PFS and OS, safety and tolerability, as well as evaluation of changes in serum levels of total and free testosterone, sex hormone binding globulins (SHBG), adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate (DHEA-S), cortisol and estradiol during orteronel treatment. As an exploratory objective, archived tumor tissue will be analyzed for the presence of phosphatidylinositol 3-kinase (PIK3CA) mutations and loss of phosphatase and tensin homolog (PTEN). Eligibility: Pts ≥18 years with AR+ (≥10% staining by immunohistochemistry) MBC, either TN or ER+ and/or PR+, are eligible. TNBC pts must have had 1-3 prior chemotherapy regimens in the advanced setting and ER+ and/or PR+ pts must have had 1-3 prior hormonal therapies and ≥1 chemotherapy regimen in the advanced setting. HER2+ pts must have received ≥2 lines of HER2-directed therapies. Additional eligibility criteria include: ECOG PS 0-2; adequate bone marrow and organ function, including left ventricular ejection fraction of ≥50%. Trial Design: Six pts will be enrolled and treated with orteronel in the lead-in phase to confirm safety and tolerability. In the absence of any safety concerns, subsequent pts will be enrolled to either Cohort 1 or Cohort 2 (described above). Cohort 1 will contain 31 pts with AR+ TNBC and Cohort 2 will contain 55 pts with AR+ ER+ and/or PR+ MBC. All pts will receive 300 mg orteronel PO BID over a 4 week cycle. Pts will be evaluated with CT scans every 2 cycles and treatment will continue until disease progression or unacceptable toxicity. Response rate and disease control rate will be presented as the point estimate along with 95% confidence interals calculated using both asymptotic normal approximation and exact binomial methods. Simon’s two-stage design will be applied using alpha=0.10 and power=0.80 for each cohort. Blood samples will be collected at baseline, on Cycle 2 Day 1, Cycle 4 Day 1, and at the end of treatment to evaluate serum total and free testosterone, SHBG, ACTH, DHEA-S, cortisol, and estradiol levels. Archival tumor samples will be collected for exploratory PTEN and PIK3CA biomarker evaluations. This trial is currently enrolling and has a total accrual goal of 86 pts. Citation Format: Denise A Yardley, Suzanne F Jones, Nancy W Peacock, Mythili Shastry, Robyn R Young, Andre M Kallab, Howard A Burris III. A phase II study with orteronel as monotherapy in patients with androgen receptor (AR) expressing metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-07.

Prostate cancer: Breaking AKR1C3-mediated enzalutamide resistance by inhibiting androgen synthesis.

Prostate cancer: Breaking AKR1C3 -mediated enzalutamide resistance by inhibiting androgen synthesis

Abstract B16: Combination of docetaxel with histone deacetylase inhibitor inhibits AR signaling synergistically in hormone-independent 22Rv1 prostate cancer cells

Abstract Globally prostate cancer is the sixth leading cause of cancer-related death in men, and it is now the first in the United Kingdom and second in the United States. At the early stage, prostate cancer growth and progression depend on androgen receptor (AR) signaling. Therefore, androgen-deprivation therapy (ADT) is effective to patient with prostate cancer by inhibition of androgen synthesis. With time, however, most patients with prostate cancer eventually lose sensitivity to androgen withdrawal and progress to the development of castration-resistant prostate cancer (CRPC). Though docetaxel is a standard of care therapy in CRPC, most of patients develop resistance to this therapy. Therefore, the novel therapeutic strategies and combination therapy are needed to overcome this resistance. In this study, we examined whether histone deacetylase inhibitor (HDACI), suberoylanilide hydroxamic acid (SAHA) might enhance the effect of docetaxel in CRPC. Hormone-independent 22Rv1 cells harboring AR were treated with docetaxel and/or SAHA. Co-treatment of docetaxel and SAHA inhibited the growth of 22Rv1 cells synergistically. Combination treatment decreased the levels of AR, prostate specific antigen (PSA), and anti-apoptotic Bcl-2 proteins (Mcl-1, Bcl-xl) more efficiently compared with docetaxel or SAHA alone, when it analyzed by Western blot. And combination treatment increased activation of caspase-3 remarkably, while docetaxel or SAHA alone increased it slightly. Moreover, immunocytochemistry and analysis of nuclear fractionated proteins showed that combination treatment induced acetylation and bundling of tubulin, inhibiting nuclear accumulation of AR significantly. These results suggested that docetaxel in combination with SAHA inhibited cell growth efficiently and induced apoptosis by repressing expression and translocation to nucleus of AR in 22Rv1 cells, and this combination can be a useful therapeutics for the treatment of CRPC patients. Citation Format: Ha-Gyeong Kim, Jung Jin Hwang, Choung-Soo Kim. Combination of docetaxel with histone deacetylase inhibitor inhibits AR signaling synergistically in hormone-independent 22Rv1 prostate cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B16.

Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention.

Androgens regulate biological pathways to promote proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen receptor (AR) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation) has been shown to activate both epithelial-to-mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types. NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen-targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.

New agents for prostate cancer.

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand. Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR downregulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone). Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab). Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent). Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogentic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited. New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit. Novel agents targeting bone metastases are being developed following the success of zoledronic acid and denosumab. Finally, all of these modalities do not appear curative, suggesting that clinical trial enrollment and a better understanding of biology remain of paramount importance.

Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer.

As prostate cancer (PCa) progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment contribute to the emergence of unique biological characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro- and macro-environment. The androgen receptor (AR) is a key gene involved in PCa etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy, antiandrogens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanism is the synthesis of constitutively active AR variants lacking the canonical ligand-binding domain. This review focuses on the etiology, characterization, biological properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.