Advanced Androgen Receptor Research Articles

Efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, correlates with the degree of AR positivity in advanced AR+/estrogen receptor (ER)+ breast cancer in an international phase 2 clinical study.

1020 Background: The AR is expressed in up to 90% of ER+ breast cancer where it acts as a tumor suppressor. Historically, therapy with synthetic androgens had efficacy, but virilizing side effects and toxicity limited their use. Enobosarm is a selective AR activating agent that does not cause masculinization and has positive attributes such as promotion of bone and improvement of physical function. In a phase 2 study, correlation between the degree of AR staining and antitumor activity in AR+/ER+ patients with metastatic breast cancer (MBC) was examined. Methods: A phase 2, open label, parallel design randomized study was conducted in 136 patients to evaluate the efficacy and safety of enobosarm in heavily pretreated women with AR+/ER+ MBC. Patients were randomized to 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. AR expression (%AR nuclei staining) in breast cancer samples was determined centrally by immunohistochemistry. The correlation between %AR staining and clinical outcomes was examined with a focus on the 9mg dose, selected for the phase 3 study and the optimal %AR staining established. Results: Tumor objective outcomes correlated with percent AR staining (Table). Further, using a 40% AR staining cutoff in patients with measurable disease, the clinical benefit rate (CBR) for ≥40% AR is 80% and <40% is 18% (p<0.0001). Best objective tumor response (BOR) in patients with ≥40% AR is 48% and <40% is 0% (p<0.0001). At ≥40% AR, median radiographic progression free survival (rPFS) is 5.47 and mean is 7.15 months vs <40% AR where the median rPFS is 2.72 and mean is 2.7 months. Similar %AR staining correlation was observed in the 18mg cohort. Enobosarm treatment was well tolerated with significant positive effects on quality of life measurements. Conclusions: Enobosarm is a novel oral selective AR activating agent in which a higher % AR staining correlates with a greater antitumor activity. By targeting and activating AR, enobosarm may represent a new hormone treatment approach for AR+/ER+ MBC. The phase 3, ARTEST trial will commence in early 2021 and randomize patients with AR+/ER+/HER2- heavily treated MBC that have progressed on a non-steroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor to receive enobosarm or standard endocrine therapy. Clinical trial information: NCT02463032 .[Table: see text]

1166P - Combined androgen blockade in patients with advanced androgen receptor-positive salivary gland carcinoma: Exploratory biomarker analyses

BackgroundA phase II trial of combined androgen blockade (CAB) in patients with advanced androgen receptor (AR)–positive salivary gland carcinoma (SGC) showed 40% of the overall response rate. However, biomarkers which predict survival in this population remain unknown. MethodsA total of 99 patients with AR–positive SGC treated with leuprorelin acetate plus bicalutamide were included. Age, sex, ECOG performance status (PS), previous treatment with trastuzumab plus docetaxel, modified Glasgow Prognosis Score (mGPS), neutrocyte-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), serum C-reactive protein (CRP) and testosterone level, HER2 status (according to ASCO/CAP Guidelines), mutational status of BRAF, PIK3CA, HRAS, AKT1 and TP53, immunohistochemistry (IHC) score of AR, Ki-67, CK5/6, p53, HER3, Akt, PI3K, FOXA1, adipophilin, mTOR and PTEN were assessed and correlated with progression-free survival (PFS) and overall survival (OS). ResultsFemale sex, mGPS (1 or 2 vs. 0), NLR (≥4.48), PLR (≥234.27), and Ki-67 labeling index (≥ 40%) were significantly associated with shorter PFS (hazard ratio [HR], 3.57, 2.01, 1.76, 1.62, and 2.16, respectively) and OS (HR, 4.91, 4.98, 3.10, 2.95, and 1.78, respectively). IHC scores of PTEN (3+) and adipophilin (≥5%) were related with favorable PFS (HR, 0.57 and 0.49, respectively) and OS (HR, 0.48 and 0.42, respectively). Age, ECOG PS, CRP, testosterone, AR positive ratio (≥70% or<70%), HER2 status, previous treatment with trastuzumab plus docetaxel, FOXA1 immunopositivity, and mutational status of BRAF, PIK3CA, HRAS, and TP53 did not have significant association with survival. ConclusionsRather than age and PS, sex and higher inflammation-based prognostic scores can serve as predictive biomarkers in patients with advanced SGC treated with CAB. IHC assessment of Ki-67, PTEN, and adipophilin may predict survival of this population. Biological validation of such markers is warranted. Clinical trial identificationUMIN000009437, Released on 03/12/2012. Legal entity responsible for the studyThe authors. FundingMEXT/JSPS. DisclosureAll authors have declared no conflicts of interest.

Development of a Transcriptional Amplification System Based on the PEG3 Promoter to Target Androgen Receptor-Positive and -Negative Prostate Cancer Cells.

Localized prostate cancer (PCa) is often curable, whereas metastatic disease treated by castration inevitably progresses toward castration-resistant PCa (CRPC). Most CRPC treatments target androgen receptor (AR) signaling. However, not all CRPC cells rely on AR activity for survival and proliferation. With advances in immunotherapy and fluid biopsies for cancer management, expression systems specific for both AR-positive and -negative PCa are required for virus-based vaccines and cell imaging. To target both AR-responsive and non-responsive cells, we developed a three-step transcriptional amplification (3STA) system based on the progression elevated gene-3 (PEG3) promoter named PEG3AP1-3STA. Notably, we report on different genetic modifications that significantly improved PEG3 promoter’s strength in PCa cells. Adenoviruses incorporating PEG3 promoter with and without transcriptional amplification systems were generated. The potential of PEG3AP1-3STA to target PCa cells was then evaluated in vitro and in vivo in androgen-responsive and non-responsive PCa cell lines. PEG3AP1-3STA was shown to be active in all PCa cell lines and not regulated by androgens, and its activity was amplified 97-fold compared to that of a non-amplified promoter. The PEG3AP1-3STA system can thus be used to target advanced AR+ and AR− cells for imaging or immunovirotherapy in advanced PCa.

Abstract OT1-05-01: A phase I/II, single arm, non-randomized study of ribociclib (LEE011), a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) is a heterogeneous disease encompassing distinct intrinsic molecular subtypes, including a luminal androgen receptor (AR) subtype, characteristically dependent on AR signaling. The AR is expressed in more than 50% of TNBCs. Bicalutamide is an oral, non-steroidal, AR antagonist, which has been studied in metastatic TNBC with a clinical benefit rate of 19% at 24 weeks. In preclinical models, cyclin dependant kinase (CDK) 4/6 inhibition has been shown to restore sensitivity to AR inhibition, and may thus be an important resistance mechanism. Ribociclib is an orally bioavailable, highly specific CDK4/6 inhibitor that induces cell cycle arrest, already approved in endocrine receptor positive breast cancers. We hypothesize that inhibition of CDK inhibition can enhance the activity of anti-androgen therapy in TNBC that express AR. Methods: We designed a phase I/II, single arm, non-randomized, open label study of the combination of bicalutamide with ribociclib in women with advanced AR-positive TNBC. The primary objective of the phase I component is to determine the maximum tolerated dose of the combination, and of the phase II component to assess the clinical benefit rate at 16 weeks. Secondary objectives include progression free and overall survival, objective response rates, and safety and tolerability. Exploratory objectives will be to assess AR quantification, localization and splice variants in circulating tumor cells, as well as quantification of pan and phospho proteins of Rb. Eligible patients must have measurable metastatic or unresectable AR-positive TNBC and have had no more than 1 line of systemic therapy for metastatic disease. The phase I study will be conducted using a 3+3 dose escalation schema, 12 to 18 patients are expected to enroll. The phase II component will utilize a Simon's two stage design, enrolling 24 patients for the first stage. At least 5 subjects must have clinical benefit by 16 weeks to proceed onto the second stage, which would enroll an additional 22 subjects for a total of 46 patients. The study will be powered to detect a clinical benefit rate of 40% with a power of 80% and a type I error rate of 10%. Contact dmusapatika@hoosiercancer.org for more information about the study. Citation Format: Santa-Maria CA, Rampurwala M, Wisinski K, Toppmeyer D, O'Regan R. A phase I/II, single arm, non-randomized study of ribociclib (LEE011), a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-05-01.

Abstract OT1-05-02: A phase II clinical trial of the combination of pembrolizumab and selective androgen receptor modulator GTx-024 in patients with advanced androgen receptor positive triple negative breast cancer

Abstract Background: Androgen receptor (AR) targeted therapy and immunotherapy represent one of the most promising strategies for metastatic triple negative breast cancer (mTNBC), which accounts for 15-20% of all breast cancers. As a nonsteroidal selective androgen receptor modulator (SARM), GTx-024 demonstrated preclinical activity in AR+ TNBC PDX model. Pembrolizumab is a highly selective humanized monoclonal antibody of the programmed cell death 1 receptor (PD-1). The complementary modes of action and low potential for overlapping toxicity make the combination promising in patients with AR+ mTNBC. Trial Design: This is an open-label Phase 2 study for AR+ mTNBC. Eligible participants receive pembrolizumab 200mg IV every 3 weeks in combination with GTx-024 18mg po daily. Eligibility Criteria: Eligible patients must have AR+ (&amp;gt;10%, 1+ by IHC) TNBC; failed up to 2 lines of therapy in metastatic setting; and have measurable disease per RECIST1.1. Patients are excluded if they have had prior checkpoint inhibitors or AR targeted agents. Patients with current or prior use of testosterone, testosterone-like agents, androgenic compounds, or anti-androgens (including systemic steroids and immunosuppressive medications)are excluded, as well as current or prior history of noninfectious pneumonitis requiring systemic steroid therapy. Specific Aims: The primary objective is to evaluate the safety/tolerability of GTx-024 and pembrolizumab and determine the response rate (CR or PR via RECIST 1.1) in patients with advanced AR+ TNBC. We will use clinical benefit rate (CBR), duration of response (DOR), PFS, and OS to test the efficacy of this novel drug combination. Statistical Design: A Simon's MiniMax two-stage Phase 2 design will be utilized. Based on the previously reported response rate associated with single agent pembrolizumab (19%), we consider a response rate of 19% for the combination as discouraging, and a 39% response rate as encouraging. As a result, we will initially accrue 15 patients (including 6 patients from safety lead-in treated at the tolerable dose). If 2 or fewer patients respond, we will stop accrual for futility. Otherwise, the study will accrue an additional 14 patients for a total of 29 patients. With 29 patients, if only 8 or fewer respond (≤27.6%), the study will be considered discouraging unless secondary evidence of clinical benefit is substantial. With more than 8 patients responding out of the 29 patients, the combination would be considered promising. This design has 85% power to declare a true response rate of 39% as promising (power), and a 10% probability of declaring a true 19% response rate as encouraging (type I error). The probability of early termination if the true response rate is 19% is 44%. Target Accrual: 29 Study Contact: Yuan Yuan MD PhD, City of Hope Comprehensive Cancer Center; Duarte, CA 91030; Email: yuyuan@coh.org Citation Format: Yuan Y, Frankel P, Synold T, Lee P, Yost S, Martinez N, Tang A, Mendez B, Schmolze D, Apple S, Hurria A, Waisman J, Somlo G, Tank N, Sedrak M, Mortimer J. A phase II clinical trial of the combination of pembrolizumab and selective androgen receptor modulator GTx-024 in patients with advanced androgen receptor positive triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-05-02.

Abstract 3781: Expression of neuroendocrine markers in circulating tumor cells from patients with prostate cancer visceral metastases

Abstract Purpose: Therapeutic resistance to Androgen Receptor (AR) targeted therapies in patients with Castration Resistant Prostate Cancer (CRPC) is complex and originates from a wide range of molecular alterations including AR point mutations, gene rearrangements and splice variant expression. An aggressive subtype of CRPC involves neuroendocrine de-differentiation that is often found in patients with visceral metastases. To evaluate neuroendocrine signatures in patients progressing on AR targeted therapies, we measured gene expression in circulating tumor cells (CTCs) as a minimally-invasive approach to examine putative resistance mechanisms to AR targeted therapies. Methods: We utilized the VERSA platform, an integrated CTC capture and analysis technology, to capture CTCs using antibodies for EpCAM or TROP2 in parallel. mRNA was extracted on chip from live cells for comparison of gene expression profiles for markers of neuroendocrine de-differentiation (SYP, CHGA, GHGB, MYCN, NCAM) and the AR signaling pathway. Fixed PBMC were stained and imaged with fluorescence microscopy and CTCs were enumerated by defining CTCs as EpCAM or TROP2 captured, intact nuclei, negative for CD45/CD11b/CD14/CD34 and cytokeratin positive. Synaptophysin or Chromogranin A protein expression was quantified in individual CTCs and compared to tumor biopsy results where available. Results: Expression of the Synaptophysin (SYP) gene was found in 39% of the patients in our initial 18 patient cohort. These patients could be split into two groups. Group 1 patients had low AR expression with minimal detection of AR target genes. Of these four patients, three had visceral metastases. Group 2 patients had high levels of AR expression including expression of the splice variants ARV7 and ARV9, and robust expression of KLK3 (PSA) and PSMA. Of these three patients, two had visceral metastases. Subsets of the patients in both groups also exhibited expression of genes identified in neuroendocrine prostate cancer including Chromogranin B, MYCN, and NCAM. A subset of the patients tested for gene expression are being screened for CTC detection of protein markers of neuroendocrine phenotypes including Chromogranin A and Synaptophysin. Conclusions: We report the first identification of neuroendocrine gene expression signatures in CTCs from patients with CRPC experiencing disease progression on advanced AR targeted therapies. These signatures may serve as predictive biomarkers of resistance to AR targeted therapies. Future studies will evaluate these signatures in prospective clinical trials. Citation Format: Jamie M. Sperger, Anupama Singh, David Niles, Charlotte N. Stahlfeld, David J. Beebe, Joshua M. Lang. Expression of neuroendocrine markers in circulating tumor cells from patients with prostate cancer visceral metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3781. doi:10.1158/1538-7445.AM2017-3781

Overall survival (OS) in patients (Pts) with diagnostic positive (Dx+) breast cancer: Subgroup analysis from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in AR+ triple-negative breast cancer (TNBC) treated with 0-1 prior lines of therapy.

1089 Background: The AR may be a novel therapeutic target for pts with AR-driven TNBC. ENZA, a potent AR inhibitor approved in men with metastatic prostate cancer, was evaluated in this phase 2 study of pts with AR+ TNBC. A genomic signature associated with AR-driven biology was identified; updated OS results in pts treated with 0-1 prior lines of therapy are presented. Methods: This is an open-label, Simon two-stage study (NCT01889238) of ENZA monotherapy in advanced AR+ TNBC (AR &gt; 0% by IHC). Bone-only disease and unlimited prior regimens were allowed; CNS metastases or seizure history were exclusionary. The primary endpoint was clinical benefit rate at 16 weeks (CBR16) in evaluable pts (AR &gt; 10% and ≥1 postbaseline assessment). OS was an exploratory endpoint. Results in intent-to-treat (ITT) and evaluable pts were presented previously (Traina TA et al. J Clin Oncol. 2015;33:1003). Results: 118 pts were enrolled (ITT). CBR16 in 78 evaluable pts was 33.3%. Of the 118 ITT pts, 56 were Dx+ and 62 were Dx–; ≥50% received 0-1 prior lines of therapy (28 Dx+, 37 Dx–). As of 26 Nov 2016 there were 83 deaths (median follow-up 28 mo); median OS (mOS) was 13 mo (95% CI; 8-18). In the Dx+ subgroup there were 32 deaths (mOS 20 mo [95% CI; 13-29]) vs 51 deaths in the Dx– subgroup (mOS 8 mo [95% CI; 5-11]). In pts with 0-1 prior lines of therapy, there were 13 deaths in the Dx+ subgroup (mOS 29 mo [95% CI; 19-not reached] vs 28 in the Dx– subgroup (mOS 10 mo [95% CI; 7-15]). The most common adverse events (AEs) were fatigue and nausea; fatigue was the only grade 3 related AE in &gt; 5% of pts. A multi-covariate Cox analysis identified Dx status (+ vs –) and line of therapy (0-1 vs ≥2) as the only variables significantly associated with OS. Conclusions: In this study, the mOS of pts with Dx+ TNBC who received 0-1 prior lines of therapy appears longer than that of unselected historic controls. ENZA may represent a therapeutic option in pts with AR+ TNBC who would otherwise receive cytotoxic chemotherapy and is currently being evaluated in ENDEAR, a phase 3 study in pts with Dx+ advanced TNBC and 0-1 prior lines of therapy. Clinical trial information: NCT01889238.

Phase (Ph) 2 stage 1 clinical activity of seviteronel, a selective CYP17-lyase and androgen receptor (AR) inhibitor, in women with advanced AR+ triple-negative breast cancer (TNBC) or estrogen receptor (ER)+ BC: CLARITY-01.

1102 Background: Seviteronel (Sevi), an oral selective CYP17-lyase and AR inhibitor that blocks testosterone and estradiol production and competitively antagonizes the AR, is in Ph 2 clinical development for BC and prostate cancer. The primary objective of this ongoing Ph 2 study (NCT02580448) is to estimate the activity of once daily Sevi in women with AR+ TNBC and ER+ BC as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wk), respectively. Methods: Patients (pts) with ER+/HER2-normal metastatic BC following progression of ≥1 prior line of endocrine therapy or TNBC were enrolled with no limit of prior therapies in either cohort. Evaluable pts had AR ≥10% via central IHC staining (TNBC only) and 1 post-baseline scan. Sevi was administered at 450 mg oral daily. Scans were performed every 8 wk. Circulating tumor cell (CTC) enumeration was performed by EPIC CTC analysis. A Simon’s 2-stage design was employed to determine activity (≥2 of 13 CBR16 in TNBC and ≥2 of 12 CBR24 in ER+ BC allow for accrual to Stage 2). Results: As of 4 Oct, 2016, 16 pts with AR+ TNBC (6 evaluable) and 14 pts with ER+ BC (11 evaluable) were enrolled. 67% had visceral metastases; 10% had stable brain metastases. 60% had ≥2 lines of prior therapy for advanced disease. 13 of 14 (93%) TNBC pts who underwent central AR testing had AR ≥10%. Four pts in the TNBC cohort and 8 pts in the ER+ cohort remain on therapy. CBR16 (TNBC) and CBR24 (ER+) was 2 of 6 (33%) and 2 of 11 (18%) allowing Stage 2 accrual in both cohorts. 7 of 10 evaluable pts with CTCs present at baseline had a CTC decline at C2D1, including all that met CBR (-94.3% [-27.5, -100] median [range]). The most common adverse events (≥ 25%) were fatigue (50%), nausea (43%) and decreased appetite (33%); all Grade 1/2. Updated CBR data will be presented at the time of presentation. Conclusions: Sevi Stage 1 activity is suggested by CBRs, along with associated CTC declines in heavily pre-treated pts with high disease burden. The observed safety profile is consistent with on-target pharmacology. Stage 2 enrollment is ongoing. Sevi may provide a novel treatment option for women with AR+ TNBC or ER+ BC. Clinical trial information: NCT02580448.

Androgen receptor-positive, triple-negative breast cancer.

Androgen receptor-positive, triple-negative breast cancer.

Phase Ib study of apalutamide (APA) with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Update on safety and efficacy.

173 Background: APA and AA target the androgenreceptor (AR) axis via different mechanisms and may have complementary activity in mCRPC. APA is an advanced AR antagonist that targets the AR ligand-binding domain with high affinity (Clegg. Cancer Res. 2012). APA prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. This phase 1b study evaluates potential PK interactions between APA and AA + P. Here we report antitumor activity and safety of APA in combination with AA + P from 57 pts versus 29 pts presented at ASCO 2015 (NCT02123758). Methods: Pts with progressive mCRPC and ECOG PS ≤ 2 received AA (1000 mg/d) + P (5 mg BID) on Cycle 1 Day 1 (C1D1) with addition of APA (240 mg/d) on C1D8 in 28-day treatment (tmt) cycles. Efficacy assessment was based on RECIST 1.1 and PCWG2 criteria. Results: 57 pts started tmt on study; median tmt duration was 17 weeks. Median age was 70 years (range, 49-89) and median baseline PSA was 111 µg/L (range, 4-2597). Bone, nodal, and visceral disease were present in 50 (88%), 31 (54%), and 17 (30%) pts, respectively. 29 (51%), 29 (51%), and 23 (40%) pts were previously treated with a taxane, AA, or enzalutamide (ENZ), respectively. 47 pts discontinued tmt: disease progression (n = 39), consent withdrawal (n = 3), physician decision (n = 1), death (n = 1), and other (n = 3). In AA- and ENZ-naïve pts (n = 18), 67% had PSA decline ≥ 50%. In AA- or ENZ-treated pts (n = 39), 15% had PSA decline ≥ 50%. Most commonly reported ( &gt; 10% of pts) drug-related AEs: fatigue (42%), diarrhea (21%), vomiting (21%), nausea (19%), hypokalemia (19%), decreased appetite (16%), hot flush (12%), abdominal pain (12%), and dysgeusia (11%). Grade ≥ 3 drug-related AEs reported in &gt; 1 pt: fatigue (7%), hypokalemia (3.5%), hyponatremia (3.5%), and hypertension (3.5%). 1 pt discontinued study drug for grade 3 fatigue. Conclusions: Interim data indicate that 240 mg/d of APA with 1000 mg/d of AA + P has antitumor activity and an acceptable safety profile in mCRPC. Clinical trial information: NCT02123758. [Table: see text]

Abstract P2-08-04: Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC)

Abstract Background: Seviteronel (Sevi), a CYP17-lyase (L) inhibitor (reduces testosterone (T) and estradiol (E2) biosynthesis) and a competitive AR antagonist, has activity in castration resistant prostate cancer at a dose of 600mg nightly. Sevi potently inhibits the growth of ER(+)/AR(+) MCF7, tamoxifen-resistant (TAMR) MCF7, and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth greater than enzalutamide (Enza), an AR antagonist (Ellison et al, SABCS 2015). Nearly all subtypes of BC, including AR(+) TNBC, are potential targets for Sevi based on its mechanism of action (MOA). Phase (Ph) 1 of this study established the recommended Ph 2 dose (RP2D) of Sevi in women with BC as 450mg once nightly, based upon preliminary tolerability and pharmacokinetics (PK) (Bardia et al, ASCO 2016). The primary objective of Ph 2 is to estimate the activity of Sevi, as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wks) for AR(+) TNBC and ER(+) BC, respectively. The secondary objectives include an estimation of Sevi tolerability and pharmacodynamics (PD) (NCT02580448). Methods: Women with advanced AR(+) TNBC (stratified by prior Enza use) or ER(+) BC were enrolled using 3 parallel Simon's 2-stage designs powered to evaluate CBR. ER(+) BC patients must have had ≥1 prior line of endocrine therapy; no limit to prior treatment for TNBC. AR(+) status was confirmed using central IHC analysis in all patients, with a ≥10% tumor cell nuclear staining cutoff for evaluable TNBC patients. Sevi was administered once nightly with dinner at 450mg (28d cycle). Tumor and blood samples were collected for PK and PD analysis (circulating tumor cells, ctDNA, sex steroids). Response was assessed every 8 wks for 52 wks, then every 12 wks thereafter. Current tolerability and PD results are presented herein for this ongoing Ph 2 study. Results: As of June 7, 2016, 17 patients received Sevi at 450mg nightly between Ph1 and Ph2 with 10 in screening. 14 patients are currently on study in Cycles 1-6. The most common adverse events (AEs &amp;gt; 10% regardless of causality or grade) were tremor (24%), pain (18%), fatigue (18%) and dyspnea (18%), nausea (12%), AST increase (12%), ALT increase (12%) and abdominal pain (12%), all of which were Grade 1 or 2 except for Grade 3 dyspnea (n=1; unrelated). No dose reductions were reported and there were no drug-related discontinuations. Nine patients underwent central AR testing (4 AR(+) of 6 TNBC; 3 AR(+) of 3 ER(+) BC). Median AR tumor cell nuclear staining was 90% (15-100%). Preliminary sex steroid analyses from 6 Ph 1 patients receiving Sevi at 450, 600, or 750mg nightly (n=2 at each dose) for 1 cycle showed a median decline in E2 concentration of 52% (-29 to -87%) to 12.4pmol/L (4 to 33pmol/L) from baseline. There was a similar magnitude of decline for T. Conclusions: Sevi was well-tolerated at 450mg nightly with exposures similar to the RP2D in men (600mg nightly). The CYP17-L inhibition activity of Sevi was demonstrated with an early and potent reduction in E2 and T. Sevi's unique CYP17-L and AR antagonist MOA may provide a new novel treatment option for AR(+) TNBC or ER(+) BC. Citation Format: Gucalp A, Bardia A, Gabrail N, DaCosta N, Danso M, Elias AD, Ali H, Lemon SJ, Riley EC, Eisner JR, Fleming RA, Kurman MR, Moore WR, Traina TA. Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-04.

Phase (Ph) 1 study of oral seviteronel (VT-464), a dual CYP17-Lyase (L) inhibitor and androgen receptor (AR) antagonist, in patients (pts) with advanced AR+ triple negative (TNBC) or estrogen receptor (ER)+ breast cancer (BC).

1088Background: Seviteronel (Sevi), a CYP17-L inhibitor (reduces androgen and estrogen biosynthesis) and AR antagonist, has activity in castration resistant prostate cancer (CRPC) at a dose of 750 mg nightly. Sevi potently and dose-dependently inhibits the growth of ER(+)/AR(+) tamoxifen-resistant (TAMR) MCF7 and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth > enzalutamide, an AR antagonist (Ellison et al. SABCS 2015). Approximately 80% of BCs, including a subset of TNBC that expresses AR, are potential targets for Sevi based on its mechanism of action (MOA). The primary objective of this Ph 1 study is to establish the recommended Ph 2 dose (RP2D) in women with BC (NCT02580448). Methods: Eligible pts have AR(+) TNBC or ER(+)/HER2-normal metastatic BC. ER(+) pts must have had ≥ 1 prior line of endocrine therapy; no limit to prior treatment for TNBC. Sevi start dose was 750 mg, administered nightly with dinner (28 d cycle) (n = 6/cohort). AR(+) status was confirmed ...

Abstract OT2-01-03: A phase 1/2 study of once-daily oral VT-464 in patients with advanced androgen receptor (AR) positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC)

Abstract VT-464, an oral dual lyase-selective CYP17 inhibitor and AR antagonist (wild-type and mutated forms [e.g., F876L and T877A]), is in multiple Phase (Ph) 2 studies as treatment for men with castration-resistant prostate cancer (CRPC). VT-464 inhibits the growth of multiple BC cell lines in vitro including MCF7 (ER(+)/AR low), tamoxifen-resistant MCF7, and MDA-MB-453 (ER(-)/AR(+)) in a dose-dependent manner and with greater potency/efficacy than enzalutamide (submitted, Ellison et al., 2015). A subset of TNBC and most ER(+) BC express AR, making them potential targets for VT-464 since it directly inhibits both androgen/estrogen synthesis and AR transcriptional activity. Objectives: The primary objective of Ph 1, now enrolling, is to establish the once-daily dose of VT-464 in women. Secondary objectives include safety, PK and efficacy endpoints, including determination of clinical benefit rate (CBR) which is the primary objective of Ph 2. Exploratory objectives include the determination of the extent of AR expression and signaling in breast tissue and to evaluate the relationship of expression with VT-464 effects on circulating tumor biomarkers, circulating hormones and clinical outcomes. Study Design: This study is an open-label, single arm, Ph 1/2 study of VT-464 in women with AR(+) TNBC or ER(+)/HER2 normal unresectable locally advanced or metastatic BC. Ph 1 will follow a modified 3+3 Fibonacci design with cohort expansion to 6 patients following a single DLT in the first 28-days of treatment. Approximately 2-3 dose-levels will be explored in Ph 1. Ph 1 start dose will be the MTD for men with CRPC. AR(+) TNBC and ER(+)/HER2 BC cohorts will be expanded in Ph 2 using the MTD from Ph 1. Ph 2 will follow a Simon's two-stage design with pre-determined futility parameters. Eligible patients will have ER≥1% BC or AR≥1% (as determined by central IHC testing using the Dako antibody) TNBC. ER(+) patients must be postmenopausal and must have received at least 1 prior line of endocrine therapy. Additional eligibility criteria include: ≥ 18 years of age, ECOG PS ≤ 1, unresectable locally advanced or metastatic BC, available representative tumor specimen to enable correlative science. Treatment Plan: Eligible patients will receive VT-464 once-nightly with dinner in a continuous dosing schedule. Adverse events and concomitant medications will be collected from the time of signing of informed consent until 30 days after end of study visit (EOS). Safety labs will be monitored monthly through EOS. Dense PK will be collected after the first dose of study drug in Ph 1 and single morning samples collected approximately every two cycles thereafter in Ph 1 and Ph 2 until EOS. Blood samples for steroids, circulating tumor DNA and circulating tumor cells will be collected through Cycle 2 and then at EOS. Tumor biopsy will be collected at baseline and at disease progression. Radiographic response will be assessed every 8 weeks and EOS. Patient Accrual: Accrual is ongoing with 12-18 patients expected to be enrolled in Ph 1. Citation Format: Gucalp A, Hudis C, Norton L, Patil S, Kurman MR, Eisner JR, Moore WR, Traina TA. A phase 1/2 study of once-daily oral VT-464 in patients with advanced androgen receptor (AR) positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC). [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 OT2-01-03.

Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC).

1003 Background: The AR may be a therapeutic target for pts with androgen-driven TNBC. ENZA, a potent AR inhibitor, is approved in men with metastatic castration-resistant prostate cancer (mCRPC) and improves median PFS compared to bicalutamide in men with mCRPC (15.7 vs 5.8 mos; HR 0.44; p 0% by IHC; NCT01889238). Pts could be prescreened for AR, and have non-measurable bone disease and unlimited prior regimens; CNS metastases or seizure history were exclusionary. The primary endpoint was clinical benefit (CR, PR or SD) at 16 wks (CBR16) in ‘Evaluable’ pts defined as having both AR IHC ≥10% and a response assessment. CBR24, PFS, response rate, and safety were assessed. An androgen-driven gene signature (Dx) was created from gene profiling and outcomes were assessed accordingly. Stage 2 enrolled if CBR16 was ≥3 of 26 Evaluable pts; H0 was rejected if CBR16 was ≥9 in 62 yielding 85% po...

13P - Stage 1 results from MDV3100-11: A 2-stage study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC)

13P - Stage 1 results from MDV3100-11: A 2-stage study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC)

Abstract P5-19-09: Preliminary results from a phase 2 single-arm study of enzalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC)

Abstract Background AR expression has been observed in 10-30% of patients with TNBC. AR+ TNBC cell lines demonstrated enhanced growth in response to androgen stimulation that is inhibited by enzalutamide (ENZA), a potent oral inhibitor of AR signaling. AR+ TNBC may represent a subtype driven by AR signaling that may respond to ENZA. Methods MDV3100-11 is an open-label, Simon 2-stage study designed to evaluate single agent ENZA (160 mg PO daily) in women with advanced AR+ TNBC (NCT01889238). Patients must have measurable or bone-only non-measurable disease. Baseline CNS imaging is required to exclude patients with CNS metastases. Patients with a seizure history are excluded. "AR+" for eligibility is defined as any nuclear AR expression by immunohistochemistry (IHC); TNBC is defined as estrogen receptor and progesterone receptor &amp;lt;1% by IHC and human epidermal growth factor receptor 2 IHC 0 or 1+ or non-amplified for IHC 2+. The primary endpoint is clinical benefit rate (CBR), defined as complete or partial response (CR or PR) or stable disease ≥16 weeks as assessed by the Investigator according to RECIST 1.1 based on the evaluable patient population. Additional endpoints include CBR at 24 weeks, response rates, safety, and tolerability. An evaluable patient is defined as having ≥10% AR staining and a postbaseline tumor assessment for response by RECIST 1.1. The study enrolls a total of 62 evaluable patients if the primary endpoint is achieved by ≥3 patients among the first 26 evaluable patients in Stage 1. Results Preliminary results are available for a subset of the first 26 evaluable patients enrolled; 14 patients have discontinued study due to progressive disease at week 16 or earlier. Eight patients have achieved the primary endpoint; 4 additional active patients have not had their week 16 assessment but achieved stable disease or better at 8 weeks. The current CBR rate is therefore 31%, and could go as high as 46% if all 4 additional patients show at least stable disease or better at their week 16 assessment. Of the 8, 2 discontinued (1 each at weeks 21 and 37), 2 had objective responses (1 PR and 1 CR), and 6 have been on study for ≥24 weeks without disease progression. The toxicity profile of ENZA is so far consistent with other hormone therapies. Full safety and efficacy data on the first 26 evaluable patients enrolled in Stage 1 will be available for inclusion at the time of the late breaking abstract. Conclusion Currently, there is no targeted therapy approved for patients with TNBC. Cytotoxics remain the standard of care in this setting. Preliminary activity and tolerability observed with ENZA are encouraging and raise the possibility that some patients with TNBC may benefit from targeted inhibition of AR signaling, thereby avoiding or delaying cytotoxic regimens. Placeholder abstract: This is a placeholder abstract; we are expecting results from the first subset of 26 evaluable patients to be ready by September 2014. Citation Format: Tiffany A Traina, Joyce O'Shaughnessy, Rita Nanda, Lee Schwartzberg, Vandana Abramson, Javier Cortes, Amy Peterson, Iulia Cristina Tudor, Martha Blaney, Joyce L Steinberg, Catherine Kelly, Maureen Trudeau, Ahmad Awada, Eric Winer, Clifford Hudis, Peter Schmid, Denise A Yardley. Preliminary results from a phase 2 single-arm study of enzalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC) [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 P5-19-09.

A phase 2 single-arm study of the clinical activity and safety of enzalutamide in patients with advanced androgen receptor-positive triple-negative breast cancer.

TPS1144 Background: Androgen receptor (AR) expression is observed in 10-30% of patients (pts) with triple-negative breast cancer (TNBC). Experiments using AR+ TNBC cell lines have demonstrated enhanced growth in response to androgen stimulation that is inhibited by enzalutamide (ENZA), a potent oral inhibitor of AR signaling (Richer JK. Abstract presented at the AACR Advances in Breast Cancer Research Meeting, San Diego, CA, 2013 October 3-6 and D'Amato NC. Abstract presented at the SABCS, San Antonio, TX, December 4-8, 2012). AR+ TNBC may represent a subtype driven by AR signaling and which may respond to ENZA. Methods: Women with advanced AR+ TNBC (ER and PgR <1% by IHC and Her2 normal) will receive daily ENZA (160 mg) until disease progression (NCT01889238). The primary endpoint (EP) is clinical benefit rate (CBR) where benefit is defined as complete or partial response (CR or PR) or stable disease (SD) ≥16 weeks (wks) as assessed by the Investigator and according to RECIST 1.1. Additional EPs include ...

Abstract OT3-2-08: A phase 2 single-arm study of the clinical activity and safety of enzalutamide in patients with advanced androgen receptor-positive triple-negative breast cancer

Abstract Background: Androgen receptor (AR) expression by IHC is observed in 10-30% of patients (pts) with triple-negative breast cancer (TNBC). Molecular profiling of TNBC has identified a subtype, luminal AR, so called as it clusters with luminal A or B on PAM50 profiling. This AR positive (AR+) subtype of TNBC expresses high levels of AR mRNA and is heavily enriched in hormone-regulated pathways, yet lacks expression of estrogen and progesterone receptors. Experiments using AR+ TNBC cell lines have demonstrated enhanced growth, both in vitro and in vivo, in response to androgen stimulation that can be inhibited by enzalutamide (ENZA), a potent inhibitor of AR signaling that lacks the agonist activity observed with bicalutamide. AR+ TNBC may represent a novel clinical subtype of breast cancer, driven by AR signaling and which may respond to ENZA. Trial design: ENZA will be administered orally at 160mg daily to pts with AR+ TNBC until disease progression or intolerability. The primary endpoint is clinical benefit rate (CBR), defined as the proportion of pts with complete response (CR), partial response (PR), or stable disease (SD) at ≥16 weeks (wks). A Simon 2-stage design is used to ensure that a minimum threshold for activity is met. If the CBR at 16 wks exceeds 2 in 26 pts, the sample size will increase to enroll 62 evaluable pts. AR testing may be performed locally for eligibility, but central testing is required in all pts. This trial is currently enrolling pts. Eligibility criteria: Eligible pts are adult women with advanced AR+ (any nuclear staining by IHC) TNBC. TNBC is determined locally and defined as &amp;lt;1% IHC staining for both ER and PgR and 0 or 1+ IHC staining for Her2 or negative for Her2 amplification in IHC 2+ disease. Advanced is defined as metastatic or locally advanced disease not amenable to curative surgery or radiotherapy. Bone-only non-measurable disease is permitted. Pts must have adequate organ and bone marrow function and ECOG status ≤1. Pts with current or previously treated brain metastases or a history of seizure are excluded, as are pts who received prior AR targeted agents for 28 or more days. Specific aims: The primary objective is to determine CBR at ≥16 wks. Secondary objectives include CBR at ≥24 wks, response rates and duration of response, progression-free survival, pharmacokinetics of ENZA, and safety and tolerability. Exploratory endpoints include overall survival and evaluation of the relationship between AR expression and signaling in breast tissue and ENZA activity. Statistical methods: Efficacy analyses will be conducted on all enrolled pts with centrally defined AR+ TNBC and at least 1 available post-baseline tumor assessment. Efficacy analyses will use investigator-assessed outcomes according to RECIST 1.1. The null hypothesis (H0), that the true CBR is 8%, will be tested against a 1-sided alternative; if CBR is &amp;lt;3 in 26 pts in Stage 1, enrollment will stop. If CBR exceeds 9 in 62 pts in Stage 2, H0 will be rejected. This design yields a 1-sided type 1 error rate of 5% and 85% power when the true response rate is 20%. Contact information: For more information on this trial, please contact Amy Peterson at Medivation (amy.peterson@medivation.com). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-08.

A Single Therapeutic miRNA Rescues the Oncolysis of Androgen Activated Prostate Specific Virus in Androgen Independent Cell Model

Prostate specific conditionally replicating adenoviruses (CRAd) are made by placing a tissue specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). However, one major problem associated with these vectors is their dependency for androgen receptor (AR), to transactivate the immediate early gene of the virus. This absolute necessity of androgens for prostate specific promoters renders them less useful in patients that have undergone or are currently on total androgen ablation therapy. Therefore, an alternative approach is needed for the existing vectors to be useful in clinical settings. To overcome this problem, we have generated a prostate specific CRAd by introducing a single therapeutic miRNA (miR-34c) that was identified in our library screen to synergize with viral oncolysis. Overexpression of miR-34c from the backbone of virus not only helped in suppressing the proliferation of AR positive cells but also rescued the oncolysis of androgen activated prostate specific virus in androgen independent cell model. To our knowledge this is the first report describing the utility of a single therapeutic miRNA construct to rescue viral oncolysis in advanced androgen resistant AR negative prostate cancer cell line model.

Androgen Receptor Mutations in High-Grade Prostate Cancer before Hormonal Therapy

Androgen action is mediated through androgen receptor (AR), which appears to undergo structural and functional alterations during prostate cancer (CaP) progression. AR mutations have been infrequently reported in CaP before hormonal therapy, but in untreated, advanced tumors AR mutations are suggested to be more common. To investigate the frequency of AR mutations in aggressive CaP before hormonal therapy, we have analyzed AR coding region for aberrations in 21 paraffin-embedded prostate carcinoma samples (14 primary tumors, 7 metastases) of poor histologic differentiation. Single-stranded conformational polymorphism and sequencing analyses revealed AR missense mutations in 29% (4/14) of the primary tumors and in one (14%) metastasis. Mutations resided in the transactivation domain and in the hinge region. One of the hinge region mutants, Ser646Phe, that was identified in a patient with short endocrine therapy response, exhibited a markedly increased transcriptional activity on single androgen response element-containing promoters. In conclusion, AR mutations are frequent in high-grade CaP before initiation of hormonal therapy, and these mutations may play a role in poor therapy response and emergence of hormone-refractory CaP in some cases.