fes serd
80054354
Abstract P1 10 04: Elacestrant, a novel oral selective estrogen receptor degrader (SERD) decreases tumoral 18F FES uptake in a phase 1 study of ER+ HER2 advanced breast cancer patients
Background: The estrogen receptor (ER) expressed in approximately 70% of breast cancers, can be mapped using 16a [18F]Fluoro 17b estradiol (FES) PET, a non invasive molecular whole body imaging tool capable of assessing ER target engagement by endocrine therapy. Elacestrant (RAD1901) is a novel, non steroidal oral SERD that has demonstrated single agent activity in heavily pre treated patients with ER+ advanced breast cancer (Bardia et al. J Clin Oncol 35, 2017: suppl; abstr 1014) The primary objective of this study was the visualization and quantification of residual ER binding with FES PET after treatment with elacestrant. Methods: In the RAD1901 106 phase 1 study (NCT02650817) patients with advanced ER+/HER2 breast cancer were treated with elacestrant at two dose levels (200 mg or 400 mg qd orally) for the first 14 days. Tumoral FES uptake was measured at baseline and day 14. After FES PET scan at day 14, all patients received elacestrant 400 mg qd until disease progression or discontinuation due to another cause. Key inclusion criteria included postmenopausal women with advanced ER+/HER2 breast cancer, who have progressed after =6 months of at least 1 line of endocrine treatment in the metastatic setting, with measurable disease according to RECIST criteria v1.1 or clinically evaluable disease. The PET scan was performed 60 min after intravenous injection of 200 MBq FES. Maximum standardized uptake values (SUVmax) were calculated and corrected for background activity. FES positive lesions had a SUVmax >1.5. FES response was defined as a 75% median decrease of SUVmax between the two scans. ESR1 mutation status was determined from circulating tumor DNA collected at multiple time points. Results: Twenty four patients were screened and 16 patients were enrolled (8 at each dose level) Median lines of prior therapy were 3, with 6 (38% patients having previously received fulvestrant and 8 (50% patients harboring at least 1 ESR1 mutation at baseline. Elacestrant demonstrated a median of 88% (range 59 97.1% reduction in tumorFES uptake following 14 days of treatment. Eleven out of 16 patients had >75% reduction in FES uptake at day 14. At the data cutoff date of 2 May 2017, median treatment duration was 8.1 weeks and 8 (50% patients remained on study. Elacestrant was generally well tolerated, with the most common treatment related adverse events (CTCAE v4.03) being low grade nausea gr1 50% gr2 =19% gr3/4 0% dyspepsia (gr1= 25% gr2 19% gr3/4 0% and dysphagia (gr1 19% gr2 =12% gr3/4 0% Updated analyses with mature data on correlation of FES uptake reduction and tumor response, treatment duration, safety and ESR1 mutation will be presented. Conclusions: Elacestrant significantly reduced FES uptake at both 200 mg and 400 mg doses after 14 days of treatment in heavily pre treated patients with advanced ER+/HER2 breast cancer, including those harboring ESR1 mutations. Citation Format: de Vries EGE, Venema CM, Glaudemans AWJM, Jager A, Menke van der Houven van Oordt CW, Neven P, Jiang H, Wang D, O9Neill A, Patki A, Aftimos P. Elacestrant, a novel oral selective estrogen receptor degrader (SERD) decreases tumoral 18F FES uptake in a phase 1 study of ER+ HER2 advanced breast cancer patients [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 P1 10 04.
Ege de Vries C M Venema Andor Wjm Glaudemans Agnes Jager C Willemien Menke-van der Houven van Oordt Patrick Neven H Jiang D Wang Alison O'Neill Abhay Patki Philippe Georges Aftimos
208446849
Dose escalation study of G1T48, an oral selective estrogen receptor degrader (SERD) in postmenopausal women with ER+/HER2 locally advanced or metastatic breast cancer (ABC)
Background The SERD fulvestrant is a well established therapy for ER+/HER2 ABC. However, its intramuscular route of administration may be painful and limits systemic exposure. G1T48 is a highly potent and efficacious oral SERD in both mutant and WT ESR1 preclinical models with the potential to achieve higher exposure and provide clinical benefit in patients with ER+ ABC. Methods Postmenopausal women with ER+/HER2 ABC following progression on endocrine therapy are eligible for this 3 3 dose escalation and expansion study. Patients receive G1T48 QD until disease progression or unacceptable toxicity. The objectives are to evaluate DLTs, safety, tolerability, PK, ER target engagement via [18F] FES PET, and anti tumor efficacy, and to determine the recommended phase 2 dose. Results Currently, 11 patients (mean age 64 years) have received G1T48 doses ranging from 200 800 mg QD for up to 7 months. Prior lines (median of 3) included chemotherapy in 45% fulvestrant in 91% and CDK4/6i in 54% of patients. G1T48 is well tolerated: no DLTs, G1T48 related SAEs, or withdrawals due to an AE have occurred. The most common Gr 1/2 G1T48 related TEAEs are diarrhea, headache, hot flush, and nausea (27% each) with a single Gr 3 TEAE (fatigue) and no Gr 4 TEAEs. G1T48 exposure increased with dose (200 to 800 mg) and minimum to moderate accumulation of G1T48 was observed following repeated doses. Median maximum standard tumor [18F] FES PET uptake values decreased (ranging from 70% (200 mg) to 88% (600 mg) after 4 weeks of treatment. Of 6 response evaluable patients (RECIST v1.1) 1 patient had a PR (600 mg, prior palbociclib/fulvestrant) and 1 patient had SD 24 weeks (200 mg, prior abemaciclib/fulvestrant) Conclusions The oral SERD G1T48 is well tolerated with no DLTs reported to date in patients with ER+/HER2 ABC. Early efficacy, safety, PK, and FES PET data are encouraging, and support continued dose escalation followed by expansion. Updated safety, anti tumor activity, and cfDNA data will be presented (NCT#03455270)
Annals of Oncology
Elizabeth Claire Dees Philippe Georges Aftimos Houven van Oordt E G E de Vries Patrick Neven Mark D Pegram Ramsha Iqbal Jorianne Boers J P Xiao Christina Sipes Changtao Li Jessica A Sorrentino Rajesh K Malik Andy Beelen C W Menke-van der
220150649
Translational strategy using multiple nuclear imaging biomarkers to evaluate target engagement and early therapeutic efficacy of SAR439859, a novel selective estrogen receptor degrader
Purpose Preclinical in vivo nuclear imaging of mice offers an enabling perspective to evaluate drug efficacy at optimal dose and schedule. In this study, we interrogated sufficient estrogen receptor occupancy and degradation for the selective estrogen receptor degrader (SERD) compound SAR439859 using molecular imaging and histological techniques. Material and methods 18 F]FluoroEstradiol positron emission tomography (FES PET) 18 F]FluoroDeoxyGlucose (FDG) PET, and 18 F]FluoroThymidine (FLT) PET were investigated as early pharmacodynamic, tumor metabolism, and tumor proliferation imaging biomarkers, respectively, in mice bearing subcutaneous MCF7 Y537S mutant ERa+ breast cancer model treated with the SERD agent SAR439859. ER expression and proliferation index Ki 67 were assessed by immunohistochemistry (IHC) The combination of palbociclib CDK 4/6 inhibitor with SAR439859 was tested for its potential synergistic effect on anti tumor activity. Results After repeated SAR439859 oral administration over 4 days, FES tumoral uptake (SUVmean) decreases compared to baseline by 35, 57, and 55% for the 25 mg/kg qd, 12.5 mg/kg bid and 5 mg/kg bid treatment groups, respectively. FES tumor uptake following SAR439859 treatment at different doses correlates with immunohistochemical scoring for ERa expression. No significant difference in FDG uptake is observed after SAR439859 treatments over 3 days. FLT accumulation in tumor is significantly decreased when palbociclib is combined to SAR439859 64% but not different from the group dosed with palbociclib alone 46% The impact on proliferation is corroborated by Ki 67 IHC data for both groups of treatment. Conclusions In our preclinical studies, dose dependent inhibition of FES tumoral uptake confirmed target engagement of SAR439859 to ERa. FES PET thus appears as a relevant imaging biomarker for measuring non invasively the impact of SAR439859 on tumor estrogen receptor occupancy. This study further validates the use of FLT PET to directly visualize the anti proliferative tumor effect of the palbociclib CDK 4/6 inhibitor alone and in combination with SAR439859.
EJNMMI Research
Laurent Besret Sebastien d'Heilly Catherine Aubert Guillaume Bluet Florence Gruss-Leleu Francoise Le-Gall Anne Caron Laurent Andrieu Sylvie Vincent Maysoun Shomali Monsif Bouaboula Carole Voland Jeffrey Ming Sebastien Roy Srinivas Rao Chantal Carrez Erwan Benjamin Jouannot
80387586
A Phase 1 study of RAD1901, an oral selective estrogen receptor degrader, in ER positive, HER2 negative, advanced breast cancer patients.
TPS627Background: RAD1901 is a novel, orally available selective estrogen receptor degrader (SERD) that binds to both mutant and wild type forms of the ER leading to ER degradation and inhibition of cellular proliferation. RAD1901 demonstrated greater growth inhibition of human breast cancer xenograft models compared to fulvestrant. In addition, RAD1901 inhibited the growth of patient derived xenograft (PDx) models harboring ESR1 mutations. RAD1901 was evaluated in a phase 1 dose escalation study (200 mg to 1000 mg of oral RAD1901 daily) in healthy postmenopausal female volunteers (N 52) They tolerated RAD1901 well and a dose proportional exposure was observed based on pharmacokinetic analyses. ER occupation was assessed using 18F fluoroestradiol positron emission tomography (FES PET) imaging which showed that after 6 days of RAD1901 treatment the mean decrease of FES uptake ER in the uterus was 83% for the 200 mg (n 3) and 92% at the 500 mg (n 4) dose levels. A previously published FES PET study,
Elisabeth G E de Vries Clasina M Venema Andor Wjm Glaudemans Lorraine A Fitzpatrick Dinesh M Purandare G Hattersley Fiona Garner
76745999
A phase I study of RAD1901, an oral selective estrogen receptor degrader, in ER positive, HER2 negative, postmenopausal advanced breast cancer patients.
TPS638 Background: RAD1901 is a novel, non steroidal, orally bioavailable selective estrogen receptor degrader (SERD) Preclinical studies demonstrated a favorable tissue selectivity profile, dose dependent ER degradation and potent inhibition of in vitro breast cancer cell proliferation. In an MCF7 xenograft model, significant tumor regression was consistently observed with RAD1901 treatment, compared to Tamoxifen or Fulvestrant. A phase I clinical study conducted in healthy postmenopausal female volunteers evaluated once daily doses up to 1000mg/day for 7 days. All dose levels were tolerated and pharmacokinetic analysis demonstrated good plasma exposure with dose proportional increases. 18F estradiol positron emission tomography (FES PET) was performed at baseline and after 6 days of treatment with RAD1901, to assess estrogen receptor engagement. Standardized uptake values (SUV) pre and post treatment demonstrated a complete attenuation of FES PET signal in ER rich tissues such as the uterus at both th.
Wael A Harb Fiona Garner Marcie Clarkin Kathleen Roberge Alan G Harris Gregory C Williams G Hattersley
4763889
Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.
In breast cancer, estrogen receptor alpha (ERa) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERa positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs) The steroid based anti estrogen fulvestrant (5) the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10) a compound in clinical development for the treatment of ERa positive breast cancer.
Journal of medicinal chemistry
George S Tria Tinya J Abrams Jason P Baird Heather E Burks Brant Firestone Larry Alex Gaither Lawrence G Hamann Guo He Christina A Kirby Sunkyu Kim Franco Lombardo Kaitlin J Macchi Donald P McDonnell Yuji Mishina John D Norris Jill Nunez Clayton Springer Yingchuan Sun Noel M Thomsen Chun-rong Wang Jianling Wang Bing Yu Choi-Lai Tiong-Yip Stefan Peukert
165053669
Abstract PD1 08: Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 for estrogen receptor positive (ER+ advanced breast cancer (ABC) with progression on endocrine therapy (ET)
Background: LSZ102 is an orally bioavailable SERD that inhibits ER gene transcription, induces receptor degradation, and blocks ER dependent cell growth in preclinical models. This study is evaluating LSZ102 as a single agent and in combination with the CDK 4/6 inhibitor ribociclib (LEE011) or the PI3K inhibitor alpelisib (BYL719) in patients (pts) with ER+ ABC. The LSZ102 single agent data are presented below; combination data are not discussed. Methods: In the dose escalation phase evaluating single agent LSZ102 (Arm A) pts (age =18 years; ECOG PS 0 1) with histologically confirmed ER+ ABC and progression on endocrine therapy (ET) received LSZ102. The starting dose was 200 mg once daily. The primary objective of Arm A was to characterize the safety and tolerability of LSZ102 and identify a recommended dose for expansion (RDE) Secondary objectives included preliminary antitumor activity and pharmacokinetics (PK) Results: As of January 22, 2018, 57 pts were enrolled to Arm A (LSZ102 200 mg, n=4; 400 mg, n=6; 450 mg fasted, n=15; 450 mg with food, n=6; 600 mg, n=20; 900 mg, n=6) Median age was 60 years, 75% (n=43) of pts had an ECOG PS of 0, 56% (n=32) had received prior fulvestrant, and 58% (n=33) had received prior CDK4/6 inhibitors; median number of prior lines of therapy (all settings) was 6. At data cut off, 48 pts had discontinued treatment, most (n=45, 94% due to disease progression. Dose limiting toxicities across treatment groups included diarrhea (2 pts in the 900 mg group) vomiting (1 pt in the 600 mg group) and AST and ALT elevation (1 pt in the 450 mg with food group) The most common treatment related adverse events (AEs) in the treatment period were diarrhea (60% nausea (56% and vomiting (30% In the treatment period, treatment related grade 3 AEs (12% were infrequent, and there were no such grade 4 events. Six pts (11% required dose reduction due to AEs (nausea, vomiting or diarrhea) 4/6 of the dose reductions occurred at 900 mg. Preliminary PK assessment showed rapid absorption and dose proportional increases in LSZ102 exposure; trough concentrations were above the predicted tumorostatic concentrations at doses of =400 mg. Based on PK results for the 450 mg fasted and fed cohorts, LSZ102 exposure does not appear to be affected by dosing with a regular meal. Evidence of ER modulation by immunohistochemistry was observed in paired baseline and on treatment biopsies. 18F fluoroestradiol positron emission tomography (FES PET) analysis (n=6) demonstrated abrogation of FES PET signal for pts in the 450 mg and 600 mg dose groups. Seventeen pts (29.8% had a best response of stable disease, and 1 pt, who happened to be in the 600 mg group, achieved a partial response. Conclusion: In heavily pretreated pts, LSZ102 was well tolerated, demonstrated antitumor activity, and achieved effective exposure levels based on PK and pharmacodynamics. Food intake did not appear to significantly alter the PK profile of LSZ102. Dose escalation for LSZ102 in combination with ribociclib or alpelisib is ongoing and will be reported in a future analysis. An update on the recommended single agent dose and schedule will be presented. Citation Format: Jhaveri K, Curigliano G, Yap Y S, Cresta S, Duhoux FP, Terret C, Takahashi S, Ulaner GA, Kundamal N, Baldoni D, Liao S, Crystal A, Juric D. Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 for estrogen receptor positive (ER+ advanced breast cancer (ABC) with progression on endocrine therapy (ET) [abstract] In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4 8; San Antonio, TX. Philadelphia (PA) AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1 08.
Poster Discussion Abstracts
Komal Jhaveri Giuseppe Curigliano Yoon Sim Yap Sara Cresta Fp Duhoux Catherine Terret S Takahashi Gary A Ulaner Nicole Kundamal Daniela Baldoni Serena Liao Adam S Crystal Dejan Juric
54150229
The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells
Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERa) gene ligand binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERa mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA's selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERa mutations.
eLife
Sean W Fanning Rinath Jeselsohn Venkatasubramanian Dharmarajan Christopher G Mayne Mostafa Karimi Gilles Buchwalter Rene Houtman Weiyi Toy Colin E Fowler Ross Han Muriel Laine Kathryn E Carlson Teresa A Martin Jason Nowak Jerome C Nwachukwu David J Hosfield Sarat Chandarlapaty Emad Tajkhorshid Kendall W Nettles Patrick R Griffin Yang Shen John A Katzenellenbogen Myles Brown Geoffrey L Greene
51930068
Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER) positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand binding domain of the ER gene (ESR1LBDm) ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD) During the first in human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. Experimental Design: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad) Results: Before starting AZD9496, 11 of 43 (25% patients had =5 CTC/7.5 mL whole blood (WB) none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC ER+ two of whom had CTC ER+ reduction. CTC Ki67 status did not change appreciably. Patients with =5 CTC/7.5 mL WB before treatment had worse progression free survival (PFS) than patients with <5 CTC (P 0.0003) Fourteen of 45 (31% patients had ESR1LBDm+ ctDNA at baseline, five of whom had =2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm+ ctDNA at C1D15 had worse PFS than patients who did not (P 0.0007) Conclusions: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on treatment changes were observed in CTC ER+ and ESR1LBDm+ ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
Clinical Cancer Research
Costanza Paoletti Gaia Schiavon Emily M Dolce Elizabeth P Darga T Hedley Carr Joseph Geradts Matthias Hoch Teresa C M Klinowska Justin P O Lindemann Gayle B Marshall Shethah R Morgan Parul Patel Vicky Rowlands Nitharsan Sathiyayogan Kimberly Aung Erika P Hamilton Manish R Patel Anne C Armstrong Komal Jhaveri Seock-Ah Im Nadia Iqbal Fouziah Butt Caroline Dive Elizabeth A Harrington J Carl Barrett Richard D Baird Daniel F Hayes
55702260
The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance
BackgroundThe oestrogen receptor (ER) is an important therapeutic target in ER positive (ER+ breast cancer. The selective ER degrader (SERD) fulvestrant, is effective in patients with metastatic breast cancer, but its intramuscular route of administration and low bioavailability are major clinical limitations.MethodsHere, we studied the pharmacology of a new oral SERD, AZD9496, in a panel of in vitro and in vivo endocrine sensitive and resistant breast cancer models.ResultsIn endocrine sensitive models, AZD9496 inhibited cell growth and blocked ER activity in the presence or absence of oestrogen. In vivo, in the presence of oestrogen, short term AZD9496 treatment, like fulvestrant, resulted in tumour growth inhibition and reduced expression of ER dependent genes. AZD9496 inhibited cell growth in oestrogen deprivation resistant and tamoxifen resistant cell lines and xenograft models that retain ER expression. AZD9496 effectively reduced ER levels and ER induced transcription. Expression analysis of short term treated tumours showed that AZD9496 potently inhibited classic oestrogen induced gene transcription, while simultaneously increasing expression of genes negatively regulated by ER, including genes potentially involved in escape pathways of endocrine resistance.ConclusionsThese data suggest that AZD9496 is a potent anti oestrogen that antagonises and degrades ER with anti tumour activity in both endocrine sensitive and endocrine resistant models.
British Journal of Cancer
Agostina Nardone Hazel M Weir Oona Delpuech Henry Brown Carmine De Angelis Maria Letizia Cataldo Xiaoyong Fu Martin J Shea Tamika Mitchell Jamunarani Veeraraghavan Chandandeep S Nagi Mark A Pilling Mothaffar F Rimawi Meghana V Trivedi Susan G Hilsenbeck Gary C Chamness Rinath Jeselsohn C Kent Osborne Rachel Schiff