Olaparib Monotherapy vs Combination Therapy for Breast Cancer

Not currently recruiting at 175 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Must not be taking: Parp inhibitors, Ddr inhibitors

Disqualifiers: Second primary cancer, Cardiac diseases, Hepatitis, 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: 3

Duration: 21-28 days per cycle, up to 32 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best use of the drug olaparib for treating triple-negative breast cancer (TNBC) that has spread and progressed despite prior treatments. Researchers compare olaparib alone to olaparib combined with Ceralasertib, an experimental treatment, to assess which is safer and more effective. The trial seeks participants with confirmed TNBC and a specific gene mutation who have undergone at least one but no more than two prior treatments for their metastatic cancer. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had cytotoxic chemotherapy, hormonal or non-hormonal targeted therapy within 21 days before starting the trial. You can continue a stable dose of bisphosphonates or denosumab for bone metastases if started at least 5 days before the study.

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

Research shows that olaparib, when used alone, is generally well-tolerated by patients with certain genetic mutations. Studies have demonstrated significant survival benefits for patients with BRCA mutations using olaparib. Most patients in these studies continued treatment without major issues.

Regarding safety with combination treatments, the study also examined adding Ceralasertib and Adavosertib to olaparib. The segment involving Adavosertib was stopped, but patients could continue taking olaparib alone. This suggests potential concerns about the safety or effectiveness of the combination. Unfortunately, clear safety information for the combination of olaparib and Ceralasertib is not available.

This trial is in Phase 2, meaning researchers are still gathering detailed safety information. Phase 2 trials aim to determine the right dose and identify any side effects, providing some level of safety assurance, though it is not complete. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer potentially novel approaches to managing breast cancer. Unlike traditional chemotherapy, which targets rapidly dividing cells, Olaparib is a PARP inhibitor that specifically targets cancer cells with defective DNA repair mechanisms, making it a more targeted therapy. The combination therapies, Olaparib with Ceralasertib and Olaparib with adavosertib, aim to enhance this effect by further disrupting cancer cell repair processes, potentially leading to improved outcomes. These approaches could provide more effective and less toxic treatment options compared to current standards.

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

This trial will compare Olaparib monotherapy with combination therapies for breast cancer. Studies have shown that Olaparib effectively treats breast cancer, especially in patients with specific BRCA gene changes. One study found that Olaparib reduced the risk of death by 32% in early breast cancer compared to a placebo. It also significantly improved the time patients lived without the cancer worsening compared to chemotherapy.

In this trial, one arm will test the combination of Olaparib and Ceralasertib, aiming to enhance Olaparib's effectiveness by targeting a protein called ATR, which may prevent cancer cells from repairing themselves. Another arm initially tested the combination of Olaparib and Adavosertib to further disrupt cancer cell repair, but this part of the study was stopped, and patients were switched to Olaparib monotherapy. Overall, Olaparib shows promise, particularly in patients with certain genetic backgrounds. ^{2 6 7 8 9}

Who Is on the Research Team?

Andrew Tutt, MB ChB PhD

Principal Investigator

Guy's Hospital, Great Maze Pond, London.

Are You a Good Fit for This Trial?

This trial is for adults with Triple-negative breast cancer (TNBC) who have measurable metastatic disease, are postmenopausal or using contraception, and have received no more than two prior chemotherapy treatments. They must not be immunocompromised, have had previous PARP inhibitor treatment, uncontrolled medical issues, brain metastases that cause symptoms, or gastrointestinal disorders affecting medication absorption.

Inclusion Criteria

My cancer is getting worse.

My breast cancer is triple-negative and has spread, with tests confirming it's not HER2 positive.

I've had 1-2 treatments with specific drugs for my advanced cancer.

Exclusion Criteria

You have been enrolled in this study before.

I have active hepatitis B or C.

You are allergic to olaparib, adavosertib, or Ceralasertib.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive olaparib monotherapy or olaparib in combination with Ceralasertib or adavosertib in a randomized setting

21-28 days per cycle, up to 32 months

Regular visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Open-label extension (optional)

Participants may opt into continuation of treatment long-term with olaparib monotherapy

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Adavosertib
• Ceralasertib
• Olaparib

Trial Overview The study compares the effectiveness of Olaparib alone versus in combination with Ceralasertib or Adavosertib in patients with TNBC stratified by tumor mutations related to DNA repair. It's an open-label trial where participants know which treatment they're getting; one arm was closed based on recommendations.

How Is the Trial Designed?

Group I: Olaparib monotherapy Active Control 1 Intervention

All randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD).

Group II: Olaparib+Ceralasertib Active Control 1 Intervention

All randomized patients will receive Olaparib 300 mg twice daily+Ceralasertib 160 mg once daily (OD).

Group III: Olaparib+adavosertib Active Control 1 Intervention

All randomized patients will receive Olaparib 200 mg BD +adavosertib 150 mg BD. Following the discontinuation of adavosertib+olaparib treatment arm on 18 April 2019, patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd).

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?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

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 a phase I study involving 79 patients, the combination of the PARP inhibitor olaparib with endocrine therapies (tamoxifen, anastrozole, or letrozole) was found to be generally safe and well tolerated, with no significant pharmacokinetic interactions between the drugs.

While tamoxifen slightly decreased olaparib exposure, the overall safety profile remained acceptable, indicating that these combinations could be a viable treatment option for patients with advanced solid tumors, including breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours. Plummer, R., Verheul, HM., De Vos, FYFL., et al.[2019]

Olaparib is an effective treatment for patients with platinum-sensitive, relapsed BRCA-mutated high-grade serous ovarian cancer, showing significant improvement in progression-free survival compared to placebo in a study of 265 patients.

The treatment is generally well tolerated, with most side effects being mild to moderate, although fatigue, anemia, and neutropenia were noted as more severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. Frampton, JE.[2016]

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]

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]

Olaparib, a PARP inhibitor, showed a 36% objective response rate in women with relapsed ovarian cancer and a germline BRCA1/2 mutation, even after they had undergone multiple lines of chemotherapy, indicating its efficacy in this challenging patient population.

The median duration of response to olaparib was 7.4 months, and the safety profile was consistent across patients who had received three or more lines of prior chemotherapy, with similar rates of serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Matulonis, UA., Penson, RT., Domchek, SM., et al.[2022]

Olaparib is an effective oral treatment for patients with BRCA mutation-positive ovarian cancer, approved for maintenance therapy after platinum-based chemotherapy, showing good tolerability with common side effects like nausea, fatigue, and anemia being mild to moderate.

Long-term monitoring is recommended due to a low risk of serious hematological complications, such as anemia and myelodysplastic syndrome, ensuring patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. Lheureux, S., Bowering, V., Karakasis, K., et al.[2015]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39544591/

Real-World Clinical Outcomes of Treatment With Olaparib ... Olaparib is effective in the treatment of metastatic breast cancer (MBC) patients, mainly confirmed by deleterious germline BRCA mutations.

2. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/lynparza-demonstrated-clinically-meaningful-prolonged-survival-benefit-in-early-breast-cancer-in-olympia-phase-iii-trial.html

LYNPARZA® (olaparib) demonstrated clinically meaningful ... 87.5% of patients treated with LYNPARZA were alive at six years vs. 83.2% in the comparator arm. First and only PARP inhibitor to improve ...

3. lynparza.com lynparza.com/breast-cancer/results/early-breast-cancer.html

Early Breast Cancer - Clinical Study Results of ... LYNPARZA lowered the risk of death by 32% in early breast cancer compared with placebo. In this study, 846 out of 921 patients treated with LYNPARZA were alive ...

4. 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.

5. astrazeneca.com astrazeneca.com/media-centre/press-releases/2024/lynparza-demonstrated-clinically-meaningful-prolonged-survival-benefit-in-early-breast-cancer-in-olympia-phase-iii-trial.html

Lynparza demonstrated clinically meaningful prolonged ... 87.5% of patients treated with Lynparza were alive at six years vs. 83.2% in the comparator arm. First and only PARP inhibitor to improve ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10948524/

Clinical effectiveness and safety of olaparib in BRCA-mutated ... The interim analysis of the phase IIIb LUCY trial demonstrated the clinical effectiveness of olaparib in patients with germline BRCA-mutated ...

7. dana-farber.org dana-farber.org/newsroom/news-releases/2024/parp-inhibition-shows-long-term-survival-benefits-for-patients-with-high-risk-brca-positive-breast-cancer

PARP Inhibition Shows Long-term Survival Benefits for ... After a median follow-up of 6.1 years, patients treated with olaparib continued to show significant improvements in survival outcomes, in both ...

8. nejm.org nejm.org/doi/full/10.1056/NEJMoa2105215

Adjuvant Olaparib for Patients with BRCA1- or BRCA2- ... Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P=0.02); however, ...

9. lynparzahcp.com lynparzahcp.com/breast-cancer/safety-tolerability/olympiad.html

gBRCAm, HER2-Negative, Metastatic Breast Cancer Learn about the safety and tolerability for LYNPARZA® (olaparib) in the OlympiAD trial for patients with gBRCAm, HER2-negative, metastatic breast cancer.