Estradiol + Olaparib for Breast Cancer

(PHOEBE Trial)

Overseen By Research Nurse

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Dickinson

Must not be taking: CYP3A inhibitors

Disqualifiers: CNS disease, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks for combination treatment, then until disease progression for single-agent treatment

6 Participants Needed

Trial Summary

What is the purpose of this trial?

Determine the safety and recommended Phase II dose of olaparib in combination with 17b-estradiol in post-menopausal patients with advanced ER+/HER2- breast cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot take other anti-cancer therapies or certain medications that affect liver enzymes (CYP3A inhibitors). You can continue bone therapies like bisphosphonates or denosumab.

What is the safety profile of estradiol and olaparib in humans?

Estradiol, used in various forms for contraception and menopause symptoms, has a generally acceptable safety profile, though it may increase the risk of blood clots and breast cancer. Olaparib, not specifically mentioned in the provided research, is known to be used in cancer treatment and has its own safety considerations. Always consult with a healthcare provider for personalized advice. ^{1 2 3 4 5}

How is the drug Estradiol + Olaparib unique for breast cancer treatment?

Estradiol + Olaparib is unique because it combines a hormone therapy (estradiol) with a targeted therapy (Olaparib), which is a PARP inhibitor that helps prevent cancer cells from repairing their DNA, potentially enhancing the effectiveness of treatment for breast cancer. ^{6 7 8 9 10}

Research Team

Mary D. Chamberlin

Principal Investigator

Dartmouth-Hitchcock Medical Center

Eligibility Criteria

This trial is for post-menopausal women with a type of breast cancer that responds to hormones but not the HER2 protein. They should have advanced stages where surgery or radiation won't cure it and must have tried at least one hormone therapy before.

Inclusion Criteria

I am a post-menopausal woman with ER+ and HER2- breast cancer.

My cancer has spread or returned and cannot be cured with surgery or radiation.

I have had hormone therapy for advanced cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 2 cycles of olaparib in combination with 17b-estradiol, followed by single-agent 17b-estradiol until disease progression

8 weeks for combination treatment, then until disease progression for single-agent treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term follow-up

Progression-free survival is measured until cancer progression or death

12 months

Treatment Details

Interventions

• 17b-estradiol
• Olaparib

Trial Overview The study tests the safety and optimal dose of Olaparib, a targeted cancer drug, when used with Estradiol, a form of estrogen. It's for patients with certain advanced breast cancers who've had previous treatments.

Participant Groups

Group I: Treatment Arm Experimental Treatment 2 Interventions

Participants receive 2 cycles of olaparib in combination with 17b-estradiol and then continue to be treated with single-agent 17b-estradiol until disease progression.

17b-estradiol is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Prevention of postmenopausal osteoporosis
• Breast cancer
• Advanced androgen-dependent carcinoma of the prostate

Approved in United States as Estradiol for:

• Moderate to severe vasomotor symptoms due to menopause
• Moderate to severe symptoms of vulvar and vaginal atrophy due to menopause
• Hypoestrogenism
• Prevention of postmenopausal osteoporosis
• Breast cancer
• Advanced androgen-dependent carcinoma of the prostate

Approved in Canada as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Prevention of postmenopausal osteoporosis
• Breast cancer
• Advanced androgen-dependent carcinoma of the prostate

Who Is Running the Clinical Trial?

Dickinson

Lead Sponsor

Trials

1

Recruited

6+

Mary D Chamberlin

Lead Sponsor

Trials

1

Recruited

6+

Gary Schwartz

Lead Sponsor

Trials

3

Recruited

30+

Dartmouth-Hitchcock Medical Center

Collaborator

Trials

548

Recruited

2,545,000+

Findings from Research

Estetrol (E4), a new estrogen used in a combined oral contraceptive with drospirenone, has demonstrated good contraceptive efficacy and a favorable safety profile in phase 3 studies, with predictable bleeding patterns.

E4 uniquely activates nuclear estrogen receptor α (ERα) without triggering membrane ERα pathways, leading to minimal effects on breast tissue proliferation and liver function, which may reduce risks associated with traditional estrogens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. Gérard, C., Arnal, JF., Jost, M., et al.[2022]

NOMAC-E2, an oral contraceptive containing nomegestrol acetate and estradiol, has been shown to be highly effective with a Pearl Index of less than one pregnancy per 100 woman-years, indicating a low failure rate.

The formulation is associated with a favorable bleeding pattern, fewer adverse events, and an acceptable safety profile, making it a promising option among oral contraceptives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nomegestrol acetate-17b-estradiol for oral contraception. Burke, A.[2021]

A comprehensive safety review of Estratest and Estratest HS, based on over 1 million woman-years of exposure from 1989 to 1996, found no significant safety concerns, with only 863 adverse events reported, which is relatively low given the extensive use.

The most common adverse events were typical of estrogen and androgen therapies, such as weight gain and headaches, and serious adverse events were rare, indicating that these medications are safe when used as directed, with manageable risks associated with their androgen component.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety surveillance of esterified estrogens-methyltestosterone (Estratest and Estratest HS) replacement therapy in the United States. Phillips, E., Bauman, C.[2019]

The study found that the estrogen 17 beta-estradiol (E2) and its metabolite 16 alpha-hydroxyestrone (16 alpha-OHE1) significantly promote the growth of estrogen receptor-positive breast cancer cells (MCF-7), with increases in colony formation of 59.4% and 105.9% respectively, indicating their potential role in tumorigenesis.

In contrast, the metabolite 2-hydroxyestrone (2-OHE1) did not promote cell growth in either in vitro or in vivo experiments, suggesting that not all E2 metabolites have the same tumor-promoting effects, and highlighting the importance of specific metabolic pathways in breast cancer progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vitro and In Vivo Modulation of Growth Regulation in the Human Breast Cancer Cell Line MCF-7 by Estradiol Metabolites. Suto, A., Telang, NT., Tanino, H., et al.[2019]

Selective estrogen receptor modulators (SERMs) and antiestrogens, such as raloxifene and bazedoxifene, are safe options for postmenopausal women as they do not increase breast cancer risk and may even offer protection against it.

The combination of conjugated estrogens with bazedoxifene has shown an improved breast safety profile compared to traditional hormone therapies, with no increase in breast density or pain over two years, indicating a safer alternative for managing menopausal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective estrogen receptor modulators and the combination therapy conjugated estrogens/bazedoxifene: A review of effects on the breast. Pickar, JH., Komm, BS.[2018]

In a study of 1063 pre/perimenopausal women with lymph-node-negative breast cancer, combining chemotherapy (CMF) with goserelin significantly improved disease-free survival (DFS) for those with estrogen receptor (ER)-positive tumors, especially in younger patients under 40.

The 12-year DFS was 77% for the CMF followed by goserelin group, compared to 69% for CMF alone and 68% for goserelin alone, indicating that the sequential therapy offers a beneficial long-term outcome for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term results of International Breast Cancer Study Group Trial VIII: adjuvant chemotherapy plus goserelin compared with either therapy alone for premenopausal patients with node-negative breast cancer. Karlsson, P., Sun, Z., Braun, D., et al.[2022]

In a study of 30 untreated prostate cancer patients, both ethinyl oestradiol combined with polyoestradiol phosphate and estramustine phosphate showed similar estrogenic effects over a 6-month follow-up period.

The treatments induced comparable changes in hormone levels, indicating that both options may be effective in managing prostate cancer through similar mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The oestrogenic effects of ethinyl oestradiol/polyoestradiol phosphate and estramustine phosphate in patients with prostatic carcinoma. A comparative study of oestrogen sensitive liver proteins, gonadotrophins and prolactin. Daehlin, L., Damber, JE., von Schoultz, B., et al.[2019]

Goserelin, a luteinizing hormone-releasing hormone analogue, has been shown to be at least as effective as cytotoxic chemotherapy for treating hormone receptor-positive early breast cancer in pre-/perimenopausal women, based on studies involving over 8000 patients.

Using goserelin can help avoid the side effects associated with traditional chemotherapy, providing a potentially safer treatment option for premenopausal patients with early breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Goserelin (Zoladex)--its role in early breast cancer in pre- and perimenopausal women. Jonat, W.[2018]

Polyestradiol phosphate, a slow-releasing depot estrogen, has shown good palliation and a 38% overall survival rate after five years in 105 male patients with prostatic carcinoma.

In a new study of 126 patients, combining polyestradiol phosphate with ethinylestradiol resulted in a significantly improved overall survival rate of 62%, suggesting that this combination therapy is more effective than using polyestradiol phosphate alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polyestradiol phosphate and ethinyl estradiol in treatment of prostatic carcinoma. Lindstedt, E.[2015]

In a study of 21 patients with prostatic carcinoma, both ethinyl oestradiol alone and in combination with polyoestradiol phosphate significantly reduced serum testosterone and other hormone levels, but the combination treatment did not provide additional benefits.

The use of ethinyl oestradiol alone resulted in fewer complications compared to the combination treatment, with some patients experiencing serious cardiovascular and liver issues when polyoestradiol phosphate was included.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Some effects of treatment with ethinyl oestradiol with or without polyoestradiol phosphate in patients with prostatic carcinoma. Tomić, R.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Nomegestrol acetate-17b-estradiol for oral contraception. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Safety surveillance of esterified estrogens-methyltestosterone (Estratest and Estratest HS) replacement therapy in the United States. [2019]

4. Japan pubmed.ncbi.nlm.nih.gov

In Vitro and In Vivo Modulation of Growth Regulation in the Human Breast Cancer Cell Line MCF-7 by Estradiol Metabolites. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Selective estrogen receptor modulators and the combination therapy conjugated estrogens/bazedoxifene: A review of effects on the breast. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Long-term results of International Breast Cancer Study Group Trial VIII: adjuvant chemotherapy plus goserelin compared with either therapy alone for premenopausal patients with node-negative breast cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

The oestrogenic effects of ethinyl oestradiol/polyoestradiol phosphate and estramustine phosphate in patients with prostatic carcinoma. A comparative study of oestrogen sensitive liver proteins, gonadotrophins and prolactin. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Goserelin (Zoladex)--its role in early breast cancer in pre- and perimenopausal women. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Polyestradiol phosphate and ethinyl estradiol in treatment of prostatic carcinoma. [2015]

10. England pubmed.ncbi.nlm.nih.gov

Some effects of treatment with ethinyl oestradiol with or without polyoestradiol phosphate in patients with prostatic carcinoma. [2019]