Olaparib
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
Olaparib: From Ovarian Cancer to Female Breast Carcinoma
One-Sentence Summary
Olaparib is an oral PARP inhibitor, originally used to treat BRCA-mutated ovarian cancer. The TxGNN model predicts it may be effective for female breast carcinoma, with 33 clinical trials and 20 publications compiled for this prediction, including several Phase 3 randomised trials in BRCA-mutated breast cancer.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Ovarian cancer (the Singapore licence records contain no approved-indication text) |
| Predicted New Indication | Female breast carcinoma |
| TxGNN Prediction Score | 99.09% |
| Evidence Level | L1 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the compiled data. Based on known information, olaparib inhibits PARP1/2 and traps PARP on DNA. In tumours with defective homologous recombination repair, such as those carrying BRCA1/2 mutations, this causes synthetic lethality: the cancer cells cannot repair the resulting DNA damage and die.
Ovarian cancer and breast cancer share this BRCA-related biology. In germline BRCA1/2-mutated breast cancer, homologous recombination repair is deficient, which is the same mechanism underlying olaparib's use in BRCA-mutated ovarian cancer. This makes the prediction mechanistically plausible. It is also consistent with the literature, which describes olaparib as approved for germline BRCA-mutated HER2-negative breast cancer.
The benefit is therefore expected mainly in biomarker-selected patients (germline BRCA1/2 or other homologous recombination gene alterations), not in all breast cancer.
Clinical Trial Evidence
Of the 33 trials compiled, the most relevant are shown below. Many are early-phase combination studies, and the compiled data contains no completed Phase 3 breast cancer registry entry. The Phase 3 breast cancer evidence comes from the publications listed in the next section.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00679783 | Phase 2 | Completed | 99 | Open-label study of olaparib (AZD2281) in BRCA-mutated breast and ovarian cancer; response rate and response markers |
| NCT04683679 | Phase 2 | Recruiting | 34 | Pembrolizumab and ablative radiotherapy with or without olaparib in metastatic triple-negative or HR+/HER2- breast cancer |
| NCT04330040 | Phase 4 | Completed | 202 | Olaparib in Indian patients with relapsed ovarian cancer and metastatic breast cancer with germline BRCA1/2 mutation (limited direct breast evidence) |
| NCT02684318 | Phase 1/2 | Unknown | 100 | Lurbinectedin (PM01183) plus olaparib in advanced solid tumours |
| NCT01623349 | Phase 1 | Completed | 118 | PI3K inhibitor (BKM120 or BYL719) plus olaparib in triple-negative breast cancer or high-grade serous ovarian cancer; safety and dosing |
| NCT01237067 | Phase 1 | Completed | 77 | Olaparib plus carboplatin in refractory or recurrent women's cancers; pharmacokinetic/pharmacodynamic run-in |
| NCT01116648 | Phase 1/2 | Active, not recruiting | 155 | Cediranib plus olaparib in recurrent ovarian or triple-negative breast cancer |
| NCT02418624 | Phase 1 | Completed | 25 | Carboplatin-olaparib followed by olaparib vs capecitabine in BRCA-mutated HER2-negative advanced breast cancer; phase 1 dose finding |
| NCT03109080 | Phase 1 | Completed | 24 | Olaparib with radiation therapy in triple-negative breast cancer |
| NCT05358639 | Phase 1 | Active, not recruiting | 36 | Olaparib plus navitoclax in triple-negative breast cancer and high-grade serous ovarian cancer |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 34081848 | 2021 | RCT | N Engl J Med | OlympiA: adjuvant olaparib in BRCA1/2-mutated early breast cancer |
| 36228963 | 2022 | RCT | Ann Oncol | OlympiA overall survival results of adjuvant olaparib in high-risk, HER2-negative early breast cancer with germline BRCA1/2 variants |
| 28578601 | 2017 | RCT | N Engl J Med | OlympiAD: olaparib in metastatic breast cancer with a germline BRCA mutation |
| 30689707 | 2019 | RCT | Ann Oncol | OlympiAD final overall survival and tolerability vs physician's-choice chemotherapy |
| 36893711 | 2023 | Phase 3 follow-up | Eur J Cancer | OlympiAD extended follow-up; median overall survival 19.3 vs 17.1 months in the final analysis (P = 0.513) |
| 33119476 | 2020 | Phase 2 trial | J Clin Oncol | TBCRC 048: olaparib in metastatic breast cancer with somatic BRCA1/2 or other homologous recombination gene mutations |
| 25366685 | 2015 | Phase 2 trial | J Clin Oncol | Olaparib monotherapy in advanced cancers with germline BRCA1/2 mutation, including breast cancer |
| 34143979 | 2021 | Phase 2 (I-SPY2) | Cancer Cell | Durvalumab plus olaparib and paclitaxel increased pathologic complete response rates in HER2-negative breast cancer |
| 32249603 | 2020 | Review | Future Oncol | Olaparib for advanced breast cancer |
| 29867226 | 2018 | Review | Br J Cancer | BRCA1/2 testing and therapeutic implications for breast cancer management |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN15662P | LYNPARZA FILM-COATED TABLET 150MG | Film-coated tablet | Not stated in the licence record |
| SIN15663P | LYNPARZA FILM-COATED TABLET 100MG | Film-coated tablet | Not stated in the licence record |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (PARP inhibitor) |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert; haematological parameters (CBC) are generally monitored for this drug class |
| Handling Protection | Please refer to the package insert and local handling regulations |
Safety Considerations
- Drug Interactions: 100 interactions were found in the drug interaction query. Major-level interactions in the listed results include:
- Aprepitant
- Dexamethasone
- Clarithromycin
Moderate-level examples include metformin, bupropion, cimetidine, miconazole, ondansetron, glyburide, repaglinide, rosuvastatin and simvastatin. Prucalopride is rated Minor.
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Randomised Phase 3 studies (OlympiA and OlympiAD) support olaparib in germline BRCA-mutated breast cancer, and the mechanism matches its established use in ovarian cancer. Evidence applies mainly to biomarker-selected patients, so use should be restricted to that group. Olaparib is already marketed in Singapore, with two registrations.
To proceed, the following is needed:
- Package insert warnings and contraindications from the HSA website, which are currently missing
- Mechanism of action data, which is currently unavailable
- Confirmation of the approved indication wording on the Singapore licences, since the licence records contain no indication text
- A germline BRCA1/2 testing pathway to select eligible patients
- A monitoring plan for haematological toxicity and for the major drug interactions (aprepitant, dexamethasone, clarithromycin)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.