Olaparib + Cediranib/Ceralasertib for Advanced Breast Cancer

Overseen By Banu Arun

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Untreated brain metastases, Active infection, Uncontrolled hypertension, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, repeated until disease progression or unacceptable toxicity

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well olaparib with cediranib or AZD6738 works in treating patients with germline BRCA mutated breast cancer that has spread to other places in the body (advanced or metastatic). Olaparib, cediranib, and AZD6738 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Do I need to stop my current medications to join the trial?

The trial requires you to stop taking any strong inhibitors or inducers of CYP3A4, with a washout period of 2 weeks for inhibitors and 4 weeks for inducers. You must also stop using natural herbal products or complementary alternative medications 7 days before starting the study drugs. Dihydropyridine calcium-channel blockers are allowed for managing hypertension. If you are on other medications, it's best to discuss with the trial team to see if they are permitted.

What data supports the idea that Olaparib + Cediranib/Ceralasertib for Advanced Breast Cancer is an effective drug?

The available research shows that Olaparib alone has been effective in treating certain types of advanced breast cancer, particularly in patients with specific genetic mutations (BRCA mutations). In the OlympiAD trial, Olaparib was shown to significantly extend the time patients lived without their cancer getting worse compared to standard chemotherapy. While there is no direct data on the combination of Olaparib with Cediranib or Ceralasertib for breast cancer, Olaparib has shown promise on its own. Additionally, the combination of Cediranib and Olaparib has been effective in treating ovarian cancer, suggesting potential benefits for breast cancer as well. ^{1 2 3 4 5}

What safety data is available for the combination of Olaparib and Cediranib/Ceralasertib in cancer treatment?

The combination of Olaparib and Cediranib has been studied in various trials, primarily in ovarian cancer. In a Phase II trial, the combination increased progression-free survival in recurrent platinum-sensitive ovarian cancer compared to Olaparib alone. The CONCERTO trial evaluated the safety and tolerability of Cediranib plus Olaparib in platinum-resistant ovarian cancer. A Phase I trial investigated the toxicities and recommended dosing of Olaparib and Cediranib in recurrent ovarian and triple-negative breast cancer. These studies provide insights into the safety profile of the combination, although specific safety data for breast cancer is limited. ^{1 2 5 6 7}

Is the drug Olaparib a promising treatment for advanced breast cancer?

Yes, Olaparib is a promising drug for advanced breast cancer. It has been shown to help patients live longer without the cancer getting worse compared to standard chemotherapy. It is especially beneficial for patients with specific genetic mutations (BRCA1/2) and those with triple-negative breast cancer. Olaparib also improves the quality of life for patients. ^{1 2 3 4 6}

Research Team

Banu Arun

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for women with advanced or metastatic breast cancer that has a BRCA mutation. They must have previously responded to PARP inhibitor treatment for at least 4 months, have good organ function, and controlled blood pressure. Pregnant or breastfeeding women can't join, nor those who've had certain treatments recently or have conditions affecting drug absorption.

Inclusion Criteria

I have taken a pregnancy test that was negative before starting the study treatment.

I am not pregnant and use effective birth control or cannot become pregnant.

My kidney function is good, based on tests.

Exclusion Criteria

I haven't had symptoms of bowel blockage in the last 3 months.

I do not have any bleeding disorders.

I have had a bone marrow or double cord blood transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive olaparib with either cediranib or ceralasertib in 28-day cycles

28 days per cycle, repeated until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 30 days post treatment

Treatment Details

Interventions

• Cediranib
• Ceralasertib
• Olaparib

Trial Overview The study tests how well olaparib works with either cediranib or AZD6738 in treating BRCA mutated breast cancer that's spread. It aims to see if these combinations can block enzymes needed for tumor growth more effectively than current treatments.

Participant Groups

Group I: Arm II (olaparib plus ceralasertib) Experimental Treatment 2 Interventions

Patients receive olaparib PO BID on days 1-28 and ceralasertib PO QD on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (olaparib plus cediranib) Experimental Treatment 2 Interventions

Patients receive olaparib PO BID and cediranib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Olaparib is already approved in European Union, United States for the following indications:

Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

In the BAROCCO trial involving 123 patients with recurrent platinum-sensitive ovarian cancer, the combination of cediranib and olaparib did not show superior progression-free survival (PFS) compared to paclitaxel chemotherapy, with median PFS of 5.6 months for the continuous cediranib-olaparib group and 3.1 months for the control group.

Despite not outperforming chemotherapy, the cediranib-olaparib combination was associated with a lower rate of treatment discontinuation due to adverse events (5% in the intermittent arm) and offers a potential non-chemotherapy treatment option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. Colombo, N., Tomao, F., Benedetti Panici, P., et al.[2022]

Olaparib, a PARP inhibitor, has shown significant clinical benefits in improving progression-free survival for patients with BRCA1 or BRCA2 mutated HER2 negative metastatic breast cancer compared to standard chemotherapy.

The drug has a manageable safety profile, making it a promising treatment option, particularly for triple negative breast cancer, although further research is needed to optimize its use with other therapies and identify suitable biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. Griguolo, G., Dieci, MV., Guarneri, V., et al.[2019]

In the phase III OlympiAD trial, olaparib significantly improved progression-free survival (PFS) in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer, with a median PFS of 8.0 months compared to 3.8 months for chemotherapy, indicating a strong efficacy of olaparib.

Subgroup analyses showed consistent benefits of olaparib across various patient characteristics, including hormone receptor status and prior chemotherapy, with higher objective response rates and improved quality of life compared to standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib efficacy in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer: Subgroup analyses from the phase III OlympiAD trial. Senkus, E., Delaloge, S., Domchek, SM., et al.[2023]

In a phase IIb trial involving 60 women with platinum-resistant recurrent ovarian cancer, the combination of cediranib and olaparib showed a modest objective response rate (ORR) of 15.3%, indicating some clinical activity in this heavily pretreated population.

The treatment was associated with significant safety concerns, as 73.3% of patients experienced grade ≥3 adverse events, highlighting the need for careful monitoring and further research into biomarkers that could predict treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. Lee, JM., Moore, RG., Ghamande, S., et al.[2023]

Olaparib, an oral PARP-inhibitor, significantly improves progression-free survival in HER2-negative advanced breast cancer patients with BRCA1/2 mutations compared to standard chemotherapy, based on a randomized Phase III trial.

The trial also indicated an overall survival benefit for patients who had not received prior chemotherapy for metastatic disease, highlighting olaparib's potential as an effective treatment option in this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib for advanced breast cancer. Griguolo, G., Dieci, MV., Miglietta, F., et al.[2021]

The combination of cediranib and olaparib was found to have significant hematologic toxicities, with 75% of patients experiencing grade 3 or higher side effects, including severe neutropenia and thrombocytopenia at the highest dose.

In terms of efficacy, the treatment showed a promising overall response rate of 44% in patients with recurrent ovarian cancer, while no clinical responses were observed in breast cancer patients, indicating that this combination may be more effective for ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Liu, JF., Tolaney, SM., Birrer, M., et al.[2021]

References

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

New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]

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

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. [2019]

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

Olaparib efficacy in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer: Subgroup analyses from the phase III OlympiAD trial. [2023]

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

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. [2023]

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

Olaparib for advanced breast cancer. [2021]

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

A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. [2021]