Estetrol (E4) for Prostate Cancer
High Dose Estetrol (HDE4) for prostate cancer treatment has successfully achieved proof-of-concept in human. The Phase II PCombi study has demonstrated promising anti-tumor activity and major improvement of quality of life in patients with advanced prostate cancer (“dual efficacy”).
The fetal estrogen estetrol (E4) is a potential new high dose estrogen (HDE) treatment for advanced prostate cancer. The term “estetrol” refers to estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, an estrogenic steroid, produced under physiological conditions only during human pregnancy by the fetoplacental unit1. It is also known as E4, referring to the four OH groups in the molecule at positions 3, 15, 16 and 17 (Fig. 1).
Pantarhei discovered the favourable pharmaceutical properties and clinical profile of this fetal estrogen. Estetrol has a high oral bioavailability and a long oral elimination half-life2. Therefore E4 is suitable as a once-a-day oral drug. It is a metabolic end product, without active and potentially toxic metabolites3. Very importantly, E4 has little interaction with liver function4 and coagulation factors5 and is expected to have a better cardiovascular (CV) safety profile compared to other natural and synthetic estrogens. Pre- and clinical E4 data collected by Pantarhei Bioscience during the first years of development have been summarised in a Supplement of Climacteric in 2008.
Androgen deprivation therapy (ADT) is central in the management of prostate cancer. The aim of ADT is to decrease testosterone (T) levels and activity, since this hormone stimulates tumor growth in hormone sensitive prostate cancer. Initial approaches to ADT included oral estrogen (i.e. diethylstilbestrol [DES]), but this treatment caused CV side effects6. The replacement of estrogens by gonadotrophin hormone-releasing (GnRH) analogues has reportedly decreased the CV risk of ADT, but causes serious estrogen deficiency, since the reduction of T suppresses its metabolite estradiol. Hot flushes occur frequently, interfering with quality of life, and increased bone turnover predisposes to bone loss and fractures. Other reported clinical symptoms of estrogen deficiency resulting from ADT are arthralgia, fatigue, mood changes, sleep disturbances, cognition problems and memory loss7-10.
The fetal estrogen E4 is a potential new endocrine treatment for advanced prostate cancer. In view of its pharmaceutical properties (no toxic metabolites, low impact on coagulation and haemostatic liver factors) and its favourable safety profile3-5, 11, 12, Pantarhei expects that E4 will be safer for the treatment of prostate cancer compared to the estrogens that have been used extensively in the past. So far, E4-related CV adverse events were uncommon in clinical studies for menopausal hormone therapy and oral contraception13-15 and in the Pantarhei studies for the oncological indications.
The objective is to develop HDE4 as part of a first line combination therapy with ADT (e.g. luteinizing hormone-releasing hormone [LHRH] agonists) in patients with locally advanced or metastatic prostate cancer. The addition of E4 to ADT is expected to improve the overall therapeutic outcome, by producing improved efficacy and reducing side effects that are typically associated with estrogen deficiency.
As an additional treatment strategy, E4 therapy can also be continued after the initial ADT treatment (18-30 months), or after progression of the disease to castrate resistant prostate cancer (CRPR). While the expected anti-tumor effect may or may not wear off at some time, the supportive care estrogen treatment advantages of E4 will remain and make HDE4 also suitable for co-treatment with anti-androgens, radiotherapy and chemotherapy.
Studies in healthy males
The safety profile and the tolerability of E4 have been evaluated in two double-blind, randomised, placebo-controlled, multiple dose studies with oral doses of 2, 5, 10, 20, 40 and 60 mg E4 in healthy males (aged 40-70 years). Estetrol was well tolerated and safe up to 60 mg given once daily during 28 days. Estetrol treatment resulted in a decrease in total T and follicle-stimulating hormone (FSH) levels, a strong decrease in free T and an increase of sex hormone-binding hormone (SHBG). Luteinizing hormone (LH) levels showed a rapid decrease after administration of E4. All changes observed were dose-dependent, but the differences between the 40 mg and the 60 mg group were small. There was a trend for a favourable estrogenic effect on LDL cholesterol (decrease). No increase in triglycerides as seen with other estrogens was observed. Changes in haemostatic variables were small in the 20 mg E4 group. In the 40 and 60 mg groups, changes were comparable to those seen with third generation oral contraceptives in women. The effects on bone markers suggest a preventive effect on bone loss. Results of this study have been presented at congresses (among others at the European Association or Urology 2017 congress and ENDO 2017 congress of the Endocrine Society) and were published in the Journal of Clinical Endocrinology and Metabolism16.
Based on the efficacy and safety results of the studies in healthy males, a dose of 40 mg E4 was selected for further combination studies with LHRH agonists in patients with prostate cancer.
The proof-of-concept PCombi study is a phase II, double-blind, randomised, placebo-controlled, multi-centre study in males recently diagnosed with locally advanced or metastatic prostate cancer, who started ADT treatment with an LHRH agonist. The two primary objectives were to assess the additional suppressive effects of HDE4 on total testosterone and free testosterone (anti-tumor effects) and its effects on hot flushes. In addition, the CV safety of HDE4 and its effect on quality of life (incl endocrine deficiency symptoms), prostate-specific antigen (PSA), endocrine parameters (including FSH, LH, dehydroepiandrosterone [DHEA]), bone turnover, lipids and safety/tolerability were investigated.
The study has been completed and results were published in European Urology Open Science (EUROS).
A scientific advisory board has been installed with the following members:
Frans Debruyne (chairman), Per-Anders Abrahamsson (Sweden), Noel Clarke (UK), David Crawford (USA), Sin Egawa (Japan), Mark Frydenberg (Australia), Marc Garnick (USA), Jeroen van Moorselaar (the Netherlands), Hein van Poppel (Belgium), Maria Ribal (Spain), Fred Saad (Canada), Neal Shore (USA) and Manfred Wirth (Germany).
List of References
1. Hagen AA, Barr M and Diczfalusy E. Metabolism of 17-beta-oestradiol-4-14-C in early infancy. Acta Endocrinol (Copenh) 1965; 49:207-220
2. Visser M, Holinka CF and Coelingh Bennink HJ. First human exposure to exogenous single-dose oral estetrol in early postmenopausal women. Climacteric 2008; 11 Suppl 1:31-40
3. Coelingh Bennink HJ, Heegaard AM, Visser M, Holinka CF and Christiansen C. Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model. Climacteric 2008; 11 Suppl 1:2-14
4. Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM and Coelingh Bennink HJ. Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur J Contracept Reprod Health Care 2015; 1-13
5. Kluft C, Zimmerman Y, Mawet M, Klipping C, Duijkers IJ, Neuteboom J, Foidart JM and Bennink HC. Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol. Contraception 2017; 95:140-147
6. Turo R, Smolski M, Esler R, Kujawa ML, Bromage SJ, Oakley N, Adeyoju A, Brown SC, Brough R, Sinclair A and Collins GN. Diethylstilboestrol for the treatment of prostate cancer: past, present and future. Scandinavian journal of urology 2014; 48:4-14
7. Cherrier MM, Aubin S and Higano CS. Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer. Psycho-oncology 2009; 18:237-247
8. Freedland SJ, Eastham J and Shore N. Androgen deprivation therapy and estrogen deficiency induced adverse effects in the treatment of prostate cancer. Prostate cancer and prostatic diseases 2009; 12:333-338
9. Allan CA, Collins VR, Frydenberg M, McLachlan RI and Matthiesson KL. Androgen deprivation therapy complications. Endocr Relat Cancer 2014; 21:T119-129
10. Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS and Smith MR. Estrogenic side effects of androgen deprivation therapy. Reviews in urology 2007; 9:163-180
11. Coelingh Bennink HJ, Holinka CF and Diczfalusy E. Estetrol review: profile and potential clinical applications. Climacteric 2008; 11 Suppl 1:47-58
12. Coelingh Bennink HJT, Verhoeven C, Zimmerman Y, Visser M, Foidart JM and Gemzell-Danielsson K. Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study. Menopause 2017; 24:677-685
13. Coelingh Bennink HJ, Verhoeven C, Zimmerman Y, Visser M, Foidart JM and Gemzell-Danielsson K. Clinical effects of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Maturitas 2016; 91:93-100
14. Gaspard U, Taziaux M, Mawet M, Jost M, Gordenne V, Coelingh Bennink HJT, Lobo RA, Utian WH and Foidart JM. A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety. Menopause 2020; 27:848-857
15. Apter D, Zimmerman Y, Beekman L, Mawet M, Maillard C, Foidart JM and Coelingh Bennink HJ. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception 2016; 94:366-373
16. Coelingh Bennink HJT, Zimmerman Y, Verhoeven C, Dutman AE, Mensinga T, Kluft C, Reisman Y and Debruyne FMJ. A Dose-Escalating Study With the Fetal Estrogen Estetrol in Healthy Men. J Clin Endocrinol Metab 2018; 103:3239-3249
17. Schmidt M, Lenhard H, Hoenig A, Zimmerman Y, Krijgh J, Jansen M and Coelingh Bennink HJT. Tumor suppression, dose-limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breast cancer. Journal of cancer research and clinical oncology 2020; doi: 10.1007/s00432-020-03472-8. Online ahead of print.