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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates the effectiveness of combining olaparib (Lynparza) with either cediranib (AZD2171) or ceralasertib for women with advanced breast cancer that has a specific genetic mutation (BRCA mutation) and has metastasized. The goal is to determine if these drugs can halt cancer cell growth by blocking essential enzymes. This trial may suit women with HER2 negative, BRCA germline positive breast cancer who have not found success with other therapies and whose condition significantly affects their daily life. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from potentially effective therapies.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining olaparib with ceralasertib is generally well-tolerated by patients. Common side effects include tiredness, nausea, and low blood cell counts, which can be managed with medical assistance. No unexpected or severe side effects were reported.

Studies also indicate that the combination of olaparib with cediranib is mostly well-tolerated. Patients experienced side effects such as high blood pressure, diarrhea, and tiredness. These effects were expected and can be managed with treatment adjustments or medication.

In summary, both treatment combinations have a manageable safety profile. While side effects do occur, they are generally not severe and can be controlled. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine olaparib with either ceralasertib or cediranib to target advanced breast cancer more effectively. Unlike standard treatments such as chemotherapy, which broadly attack cancer cells, olaparib is a PARP inhibitor that specifically exploits weaknesses in the cancer cell's DNA repair machinery. Adding ceralasertib, which inhibits the ATR protein, or cediranib, which blocks blood vessel growth, enhances the attack by cutting off cancer's survival pathways. This dual approach aims to produce a more powerful and precise treatment, potentially leading to better outcomes for patients with fewer side effects.

What evidence suggests that this trial's treatments could be effective for advanced breast cancer?

This trial will compare two treatment combinations for advanced breast cancer. Studies have shown that using olaparib with ceralasertib, one of the combinations in this trial, effectively treats patients with BRCA-mutated breast cancer. In these patients, 35% had a confirmed positive response, with some experiencing complete tumor shrinkage. Patients taking olaparib alone or with ceralasertib lived longer than those receiving traditional chemotherapy.

Research has also shown promising results for the combination of olaparib and cediranib, the other combination being tested in this trial. Participants taking this combination had a median progression-free survival of 5.1 months, meaning the cancer did not worsen during this time. These combinations work by targeting enzymes that help cancer cells grow, which helps stop the cancer from spreading. ^{6 7 8 9 10}

Who Is on the Research Team?

Banu Arun

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

Citations

1. lynparza.com lynparza.com/breast-cancer/results/metastatic-breast-cancer.html

Metastatic Breast Cancer - Clinical Study Results of ... LYNPARZA lowered the risk of cancer growing or spreading, or death by 42% compared with certain chemotherapies. 52% of people who took LYNPARZA and 23% of ...

2. lynparzahcp.com lynparzahcp.com/breast-cancer/efficacy/olympiad.html

LYNPARZA® (olaparib) Efficacy for gBRCAm, HER2-negative ... LYNPARZA significantly improved PFS vs physician's choice of chemotherapy in the OlympiAD trial. 1,2 Primary endpoint: progression-free survival.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9527502/

Cediranib in Combination with Olaparib in Patients without a ... Median progression-free survival was 5.1 months, and overall survival was 13.2 months. Cediranib plus olaparib showed activity in subsets of heavily pretreated, ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.9065

A phase II study of cediranib in combination with olaparib ... Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumors carrying a germline BRCA mutation. We ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01116648

NCT01116648 | Cediranib Maleate and Olaparib in ... Cediranib maleate may help keep cancer cells from growing by affecting their blood supply. Olaparib may stop cancer cells from growing abnormally. The ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8265343/

Clinical Activity and Safety of Cediranib and Olaparib ... Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04090567

NCT04090567 | Olaparib With Cediranib or AZD6738 for ... 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 ...

8. cancer.gov cancer.gov/clinicaltrials/NCT02889900?cid=eb_govdel

Efficacy and Safety Study of Cediranib in Combination With ... This is an open label, single arm, multi-center study to assess the efficacy and safety of the combination of cediranib and olaparib tablets in ...

9. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D8488C00001

Efficacy and Safety Study of cediranib in combination with ... This is an open label, single arm, multi-center study to assess the efficacy and safety of the combination of cediranib and olaparib tablets in ...

10. dana-farber.org dana-farber.org/clinical-trials/18-714

"A Phase 2 Study of Cediranib in Combination with ... This phase II trial studies cediranib maleate in combination with olaparib in treating patients with solid tumors that have spread to other parts of the ...