Olaparib Monotherapy vs Combination Therapy for Breast Cancer

Recruiting at 148 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

273 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Olaparib for breast cancer?

Olaparib has shown clinical benefits for patients with advanced breast cancer, particularly those with specific genetic mutations (BRCA1/2), by prolonging the time the cancer does not worsen compared to standard chemotherapy. It is also approved for early high-risk breast cancer with similar genetic mutations, indicating its effectiveness in both early and advanced stages of the disease. ^{1 2 3 4 5}

Is Olaparib safe for use in humans?

Olaparib, used for breast cancer treatment, has shown a manageable safety profile in clinical trials, meaning side effects are generally tolerable. It has been tested both alone and in combination with other therapies, and while it can cause side effects, these are typically manageable with medical supervision. ^{1 2 3 5 6}

How is the drug Olaparib unique in treating breast cancer?

Olaparib is unique because it is an oral medication specifically effective for breast cancer patients with BRCA gene mutations, offering a targeted approach that improves progression-free survival compared to standard chemotherapy, especially in triple-negative breast cancer cases. ^{2 3 4 5 7}

What is the purpose of this trial?

This study is to assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (Ceralasertib \[AZD6738\]) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib \[AZD1775\]) in second or third line setting in patients with Triple-negative breast cancer (TNBC) prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the homologous recombination repair (HRR) pathway. Treatment arms are olaparib monotherapy, olaparib+ Ceralasertib and olaparib+adavosertib. The study subject population will be divided into Stratum A, Stratum B, and Stratum C. Due to the different schedules of administration of each of the treatment options as well as their different toxicity profiles, the study is not blinded. Study has two stage consent process- stage 1 consent (molecular screening for HRR defects) and stage 2 consent (main study). Patients with TNBC and with known qualifying BRCAm, non BRCAm HRRm and non HRRm status will be offered the option of consenting to the main part of the study within the 28-day screening period. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd). Following the closure of this arm the total number of patients randomised will be lower (approximately 350 patients). Approximately 300 patients will be randomised (using randomisation ratio 1:1) to 2 ongoing treatment arms plus an additional 47 patients to a 3rd arm (olaparib+adavosertib) prior to the arm being discontinued.

Research Team

Andrew Tutt, MB ChB PhD

Principal Investigator

Guy's Hospital, Great Maze Pond, London.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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, 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 (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]

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]

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, 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 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]

References

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

Olaparib for advanced breast cancer. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. [2019]

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

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

4. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. [2015]

5. United States 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. [2019]

6. England 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. [2022]

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

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