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SERDs in HR+HER2- Breast Cancer
- 1. SERDs (Selective Estrogen Receptor Degrader) in HR+/HER2- Breast Cancer BY: PRANAY KUMAR
- 2. Table of Contents ❖ Executive Summary ❖ What is HR+/HER2- Breast Cancer ❖ What is SERD’s ❖ SERD’s Mechanism of action relative to HR+/HER2- Breast Cancer ❖ Why are SERD’s important ❖ SERD’s Role And Where Are They Best Positioned In The Treatment Paradigm ❖ Clinical Landscape ❖ Clinical Strategies Are Being Evaluated For SERDs ❖ Key SERD’s In Clinical Development ❖ Key Insight
- 3. Executive Summary Key Players Key Insight Clinical Trial Focus • G1 Therapeutics • Sanofi • Zeno Alpha • Novartis • AstraZeneca • Radius Pharmaceuticals • Hoffmann-La Roche • Borstkanker Onderzoek Groep • In coming years Roche, Radius, and Borstkanker are going to capture the market of SERDs (Selective Estrogen Receptor Degrader) in HR+/HER2- Breast Cancer. SERD’s in HR+/HER2- Breast Cancer • All the clinical trial are focused on 1st and 2nd line of therapy. Some of the players are also exploring the 3rd line of therapy. • Combination therapies are focused by industry players.
- 4. What is HR+/HER2- Breast Cancer • Breast cancer is a type of cancer that starts in the breast. Cancer starts when cells begin to grow out of control. • Breast cancer cells taken out during a biopsy or surgery will be tested to see if they have certain proteins that are estrogen or progesterone receptors. • The hormones estrogen and progesterone attach to these receptors, they fuel the cancer growth. • Cancers are called hormone receptor-positive or hormone receptor-negative based on whether or not they have these receptors (proteins). HER2-negative: • HER2 is short for human epidermal growth factor receptor 2. • HER2 is sometimes called ERBB2, which stands for Erb-B2 receptor tyrosine kinase 2. • HER2 is a gene that produces HER2 proteins, or receptors. HR+: • HR is short for hormone receptor. Breast tumors are tested for both estrogen receptors (ER) and progesterone receptors (PR). • These breast cancers can be treated with hormone therapy drugs that lower estrogen levels or block estrogen receptors. Source: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html, https://www.healthline.com/health/breast-cancer/understanding-managing/understanding-hr-breast-cancer-diagnosis#What-HER2-negative-means
- 5. What is SERD’s • SERD’s - Selective estrogen receptor degrader OR Selective estrogen receptor downregulators. • SERD’s are pure anti-estrogens. • A novel class of compounds capable of reducing the ERα protein level and blocking ER activity. • SERDs are considered as a significant therapeutic approach to treat ER+ breast cancer in both early stage and more advanced drug-resistant cases. • SERD for the treatment of breast cancer in patients who have progressed on antihormonal agents, several molecules with diverse chemical structures have been rapidly developed, studied and evaluated for selective estrogen receptor downregulation activity. • Fulvestrant is a first-generation SERD approved by FDA, indicated for metastatic/advanced HR+ breast cancer. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508469/, https://www.x-mol.com/paper/1236082111706546176
- 6. SERD’s Mechanism of action relative to HR+/HER2- Breast Cancer Source: https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.2095, https://www.clinical-breast-cancer.com/article/S1526-8209(11)70479- 7/fulltext#:~:text=When%20fulvestrant%20binds%20to%20estrogen,results%20in%20pure%20antiestrogenic%20effects. SERD’s mechanism of action: • Binds ER to prevent estrogen binding its receptor thereby inhibiting ER signaling. • Degrades ER. SERD’s (fulvestrant): • Binds to estrogen receptor monomers it inhibits receptor dimerization, activating function 1 (AF1) and AF2 are rendered inactive, translocation of receptor to the nucleus is reduced, and degradation of the estrogen receptor is accelerated. This results in pure antiestrogenic effects. Figure: Representation of the action of fulvestrant. AF1, activation function 1; AF2, activation function 2; ER, estrogen receptor; ERE, estrogen receptor response element; F, fulvestrant; RNA POL II, ribonucleic acid polymerase II.
- 7. Why are SERD’s important Source: https://www.nature.com/articles/s41416-018-0354-9#:~:text=Background,bioavailability%20are%20major%20clinical%20limitations., Raising the need for a novel oral SERD with a more favorable bioavailability profile. SERD’s inhibits receptors dimerization. SERD’s is a potent anti-oestrogen that antagonises and degrades ER with anti-tumour activity in both endocrine-sensitive and endocrine-resistant models.
- 8. SERD’s Role And Where Are They Best Positioned In The Treatment Paradigm Source: https://pubmed.ncbi.nlm.nih.gov/31562570/ SERD approved by the FDA as a drug for the treatment of breast cancer, and several non-steroidal molecules such as RAD- 1901, AZD-9496 and GDC- 0927 etc. SERD’s work as first- or second- line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3- kinase inhibitors for the treatment of metastatic breast cancer. SERDs emerged as one of the possible approaches to treat drug- resistant breast cancer. SERD’s act as a pure antagonist by interfering with the binding of estradiol to estrogen receptors (ERs) and inducing the rapid downregulation of ER.
- 9. Clinical Landscape Source:https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=SERD+OR+selective+estrogen+receptor+degrader+OR+selective+estrogen+receptor+downregul ator&cntry=&state=&city=&dist= Sample size: 8 studies have been taken into consideration to derive the insight. 2 1 2 3 Phase Analysis Not Applicable Phase 1 Phase 1|Phase 2 Phase 2 Phase 2|Phase 3 Phase 3 Phase 4 Blanks 8 Studies 2 6 Status Analysis Completed Active, not recruiting Not yet recruiting Recruiting Terminated Unknown status Withdrawn 8 Study Results Analysis Has Results No Results Available Key Takeaways • Major companies and academics institute clinical trials are in phase 2, phase 3 targeting the breast cancer treatment. 8 Studies 8 Studies 1/6
- 10. Clinical Landscape Source:https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=SERD+OR+selective+estrogen+receptor+degrader+OR+selective+estrogen+receptor+downregul ator&cntry=&state=&city=&dist= Sample size: 8 studies have been taken into consideration to derive the insight. Key Takeaways • Zeno Alpha Inc. phase 1|phase 2 (ZN-c5) focusing on treatment of breast cancer with 458 enrollment. 1 1 1 1 2 2 0 0.5 1 1.5 2 2.5 3 3.5 Not Applicable Phase 1 Phase 1|Phase 2 Phase 2 Phase 2|Phase 3 Phase 3 Phase 4 Blanks Phase Vs Status Analysis Completed Active, not recruiting Not yet recruiting Recruiting Terminated Unknown status Withdrawn 2/6
- 11. Clinical Landscape Source:https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=SERD+OR+selective+estrogen+receptor+degrader+OR+selective+estrogen+receptor+downregul ator&cntry=&state=&city=&dist= Sample size: 8 studies have been taken into consideration to derive the insight. Key Takeaways • Radius Pharmaceuticals, Inc., Hoffmann-La Roche, and Borstkanker Onderzoek Groep is the leading player and all the clinical studies are in phase 3 targeting the potential market. 1 1 1 1 1 1 1 1 0 0.2 0.4 0.6 0.8 1 1.2 Key Players Analysis 1 1 1 1 1 1 1 1 0 2 Players Vs Status Analysis Completed Active, not recruiting Not yet recruiting Recruiting Terminated Unknown status Withdrawn 1 1 1 1 1 1 1 1 0 0.5 1 1.5 Players Vs Phase Analysis Not Applicable Phase 1 Phase 1|Phase 2 Phase 2 Phase 2|Phase 3 Phase 3 Phase 4 Blanks 3/6
- 12. Clinical Landscape Source:https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=SERD+OR+selective+estrogen+receptor+degrader+OR+selective+estrogen+receptor+downregul ator&cntry=&state=&city=&dist= NCT Number Title Status Conditions Interventions Phases Enrollment Line of Therapy Sponsor/Col laborators NCT03455270 G1T48, an Oral SERD, Alone and in Combination With Palbociclib in ER- Positive, HER2-Negative Advanced Breast Cancer Recruiting Carcinoma, Ductal, Breast|Breast Cancer Female|Breast Neoplasm|Breast Cancer|Metastatic Breast Cancer|Advanced Breast Cancer|Stage IV Breast Cancer Drug: G1T48|Drug: Palbociclib Phase 1 184 1st line therapy G1 Therapeutics, Inc. NCT03560531 Drug: ZN-c5|Drug: Palbociclib Recruiting Breast Cancer Drug: ZN- c5|Drug: Palbociclib Phase 1|Phase 2 458 2nd line therapy Zeno Alpha Inc. NCT02734615 Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers Active, not recruiting Advanced or Metastatic ER+ Breast Cancer Drug: LSZ102|Drug: LEE011|Drug: BYL719 Phase 1 200 2nd line therapy Novartis 4/6
- 13. Clinical Landscape Source:https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=SERD+OR+selective+estrogen+receptor+degrader+OR+selective+estrogen+receptor+downregul ator&cntry=&state=&city=&dist= NCT Number Title Status Conditions Interventions Phases Enrollment Line of Therapy Sponsor/Col laborators NCT04191382 Phase 2 Window Study of SAR439859 Versus Letrozole in ER+, HER2- Pre-operative Post- menopausal Primary Breast Cancer (AMEERA-4) Recruiting Breast Cancer Drug: SAR439859|Dru g: letrozole Phase 2 126 2nd line therapy Sanofi NCT04214288 A Comparative Study of AZD9833 Versus Fulvestrant in Women With Advanced ER- Positive HER2-Negative Breast Cancer Recruiting Advanced ER-Positive HER2-Negative Breast Cancer Drug: AZD9833|Drug: Fulvestrant Phase 2 288 2nd line therapy AstraZeneca 5/6
- 14. Clinical Landscape Source:https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=SERD+OR+selective+estrogen+receptor+degrader+OR+selective+estrogen+receptor+downregul ator&cntry=&state=&city=&dist= NCT Number Title Status Conditions Interventions Phases Enrollment Line of Therapy Sponsor/Col laborators NCT03778931 Phase 3 Trial of Elacestrant vs. Standard of Care for the Treatment of Patients With ER+/HER2- Advanced Breast Cancer Active, not recruiting Breast Cancer Drug: Elacestrant|Drug: Standard of Care Phase 3 466 2nd line therapy Radius Pharmaceuticals, Inc. NCT04546009 A Study Evaluating the Efficacy and Safety of GDC-9545 Combined With Palbociclib Compared With Letrozole Combined With Palbociclib in Participants With Estrogen Receptor- Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer Recruitin g Estrogen Receptor- Positive, HER2- Negative Locally Advanced or Metastatic Breast Cancer Drug: GDC- 9545|Drug: GDC- 9545-matched Placebo|Drug: Letrozole|Drug: Letrozole-matched Placebo|Drug: Palbociclib|Drug: LHRH Agonist Phase 3 978 1st line therapy Hoffmann-La Roche NCT03425838 Endocrine Therapy Plus CDK4/6 in First or Second Line for Hormone (SONIA) Receptor Positive Advanced Breast Cancer Recruitin g Breast Neoplasm Female Drug: CDK 4/6 inhibitor|Drug: Non-Steroidal Aromatase Inhibitor|Drug: Fulvestrant Phase 3 1050 1st or 2nd line therapy Borstkanker Onderzoek Groep 6/6
- 15. Clinical Strategies Are Being Evaluated For SERDs Source: https://www.precisiononcologynews.com/cancer/eli-lilly-zentalis-pharma-partner-study-selective-estrogen-receptor-degrader-verzenio-combo#.X7aJC2gzZPY, https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.2095 • The combination with mTOR inhibitor, everolimus, and CDK 4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) are noted as emerging therapy for patients with HR+/HER2− BC. • For Instances, In July 2020, Zentalis Pharmaceuticals collaborated with Eli Lilly to evaluate Zentalis' ZN-c5, an investigational oral selective estrogen receptor degrader (SERD), in combination with Lilly's CDK4/6 inhibitor abemaciclib (Verzenio), in patients with estrogen receptor-positive, HER2- negative, advanced breast cancer. Zentalis is responsible for conducting the study involving the combination therapy. Lilly will provide all required doses of abemaciclib, and Zentalis will maintain full ownership of ZN-c5. • Monotherapy is successful in treating majority of patients with HR+/HER2− BC. Treating the patient suffering from postmenopausal women with ER+, advanced or metastatic BC, either for disease relapse, on or after adjuvant antiestrogen therapy or for disease progression following endocrine therapy. • In SERD’s studies by industry players and other players (academic, individual) are focusing on monotherapy and in combination both.
- 16. Key SERD’s In Clinical Development Source: https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.1070, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/giredestrant, https://adisinsight.springer.com/drugs/800050643, https://www.futuremedicine.com/doi/full/10.2217/fon-2019-0370 Sponsor/Co llaborators NCT Number Title Conditions Interventions Type Analysis Radius Pharmaceuticals, Inc. NCT03778931 Elacestrant vs. Standard of Care for the Treatment of Patients With ER+/HER2- Advanced Breast Cancer Breast Cancer Drug: Elacestrant|Drug: Standard of Care Postmenopausal , vs SoC The elacestrant can be use as monotherapy and combination therapies in 2nd or 3rd line therapy for the patients with ER+/HER2- advanced or metastatic breast cancer. Hoffmann-La Roche NCT04546009 A Study Evaluating the Efficacy and Safety of GDC-9545 Combined With Palbociclib Compared With Letrozole Combined With Palbociclib in Participants With Estrogen Receptor-Positive, HER2- Negative Locally Advanced or Metastatic Breast Cancer Estrogen Receptor- Positive, HER2- Negative Locally Advanced or Metastatic Breast Cancer Drug: GDC- 9545|Drug: GDC- 9545-matched Placebo|Drug: Letrozole|Drug: Letrozole- matched Placebo|Drug: Palbociclib|Drug: LHRH Agonist Postmenopausal The combination therapy is the emerging treatment option for patient suffering from breast cancer. Sanofi NCT04191382 Study of SAR439859 Versus Letrozole in ER+, HER2- Pre- operative Post-menopausal Primary Breast Cancer (AMEERA-4) Breast Cancer Drug: SAR439859|Drug : letrozole Postmenopausal , vs letrozole The drug molecules are showing favorable safety profile with limited TRAEs (treatment-related adverse events).
- 17. Key Insight Strategic Initiatives To Boost Revenue • Expansion of distribution channel in the different geographical regions. • Pricing strategy to capture major market share. • Strategic partnerships to increase revenue generation. • Increasing brand awareness among healthcare professionals. Clinical Insights • Players are targeting on both the option: monotherapy and combination therapies for the patients with ER-positive, HER2- negative, advanced or metastatic breast cancer. • Drug like “abemaciclib” which is prescribed in combination with hormonal therapy, including fulvestrant, the only FDA-approved SERD, to treat patients with ER-positive, HER2-negative advanced or metastatic breast cancer following endocrine therapy.
- 18. Thanks!