Olaparib
| 證據等級: L5 | 預測適應症: 1 個 |
目錄
Olaparib: From Ovarian Cancer to Breast Cancer
One-Sentence Summary
Olaparib is a PARP1/2 inhibitor originally developed for maintenance treatment of platinum-sensitive relapsed, BRCA-mutated high-grade serous ovarian, fallopian tube, or peritoneal cancer. The TxGNN model predicts it may also be effective for Female Breast Carcinoma, a prediction already strongly corroborated by 80 clinical trials and 20 publications, including two landmark Phase III RCTs (OlympiAD, OlympiA) that have led to approved breast cancer indications for olaparib in other jurisdictions.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Ovarian cancer — maintenance treatment of platinum-sensitive relapsed, BRCA-mutated high-grade serous epithelial ovarian/fallopian tube/peritoneal cancer |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.09% |
| Evidence Level | L1 |
| New Zealand Market Status | ✗ Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Olaparib is a PARP1/2 (poly ADP-ribose polymerase) inhibitor. It blocks base-excision repair of single-strand DNA breaks, which in tumour cells carrying BRCA1/2 germline mutations (i.e. homologous recombination deficiency, HRD) leads to synthetic lethality — the cancer cell, already unable to repair double-strand breaks via homologous recombination, cannot compensate for the loss of the base-excision pathway either, and dies. Normal cells retain functional homologous recombination repair and are largely spared.
Ovarian cancer and breast cancer share the same underlying genetic vulnerability: both are core BRCA1/2-associated malignancies, and BRCA-mutated tumours in either tissue rely on the same DNA-repair deficiency that olaparib exploits. This mechanistic overlap is why the TxGNN prediction is biologically plausible rather than a spurious network association — the drug does not need a breast-specific mechanism, only a BRCA/HRD-positive tumour, which occurs in both cancer types.
This is also not a purely theoretical extrapolation: olaparib has already progressed through Phase III confirmatory trials in breast cancer (OlympiAD for metastatic disease, OlympiA for high-risk early-stage adjuvant use) and holds approved breast cancer indications in other regulatory jurisdictions (FDA, EMA), which independently validates the repurposing rationale identified by the model.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02282020 | Phase 3 | Completed | 266 | OlympiAD: Olaparib vs physician's choice chemotherapy in gBRCA-mutated, HER2-negative metastatic breast cancer |
| NCT00679783 | Phase 2 | Completed | 99 | Early AZD2281 (olaparib) study establishing response rate in BRCA-mutated/triple-negative breast cancer, foundational for later Phase III design |
| NCT04330040 | Phase 4 | Completed | 202 | Post-marketing real-world study in Indian patients with platinum-sensitive relapsed ovarian cancer and gBRCA1/2-mutated metastatic breast cancer |
| NCT02418624 | Phase 1 | Completed | 25 | Carboplatin-olaparib sequencing vs capecitabine as first-line therapy in BRCA1/2-mutated HER2-negative advanced breast cancer |
| NCT05498155 | Phase 2 | Active, not recruiting | 50 | Neoadjuvant olaparib monotherapy vs olaparib + durvalumab in BRCA-mutated, early-stage HER2-negative breast cancer |
| NCT03109080 | Phase 1 | Completed | 24 | Olaparib combined with radiation therapy in inflammatory/locoregionally advanced/metastatic or residual triple-negative breast cancer |
| NCT01623349 | Phase 1 | Completed | 118 | Oral PI3K inhibitor (BKM120/BYL719) plus olaparib in recurrent triple-negative breast cancer or high-grade serous ovarian cancer |
| NCT02624973 | Phase 2 | Active, not recruiting | 200 | PETREMAC: personalized treatment strategies in high-risk breast cancer using predictive biomarkers |
| NCT04041128 | Early Phase 1 | Completed | 14 | Pre-surgical window study of PARP inhibition on cellular/molecular changes in primary ovarian and breast cancer |
| NCT05209529 | Phase 2 | Withdrawn | 0 | Neoadjuvant olaparib + durvalumab for BRCA-associated triple-negative breast cancer (did not proceed) |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36228963 | 2022 | RCT | Annals of Oncology | OlympiA: overall survival results of adjuvant olaparib in gBRCA1/2-mutated, high-risk early breast cancer |
| 34081848 | 2021 | RCT | New England Journal of Medicine | OlympiA primary results: adjuvant olaparib reduces recurrence in BRCA1/2-mutated early breast cancer |
| 28578601 | 2017 | RCT | New England Journal of Medicine | OlympiAD primary results: olaparib shows antitumor activity in metastatic breast cancer with germline BRCA mutation |
| 30689707 | 2019 | RCT | Annals of Oncology | OlympiAD final overall survival and tolerability vs chemotherapy of physician's choice |
| 36893711 | 2023 | RCT | European Journal of Cancer | OlympiAD extended follow-up confirming survival and safety profile |
| 33119476 | 2020 | Phase 2 Trial | Journal of Clinical Oncology | TBCRC 048: olaparib activity in metastatic breast cancer with somatic BRCA or other homologous recombination gene mutations |
| 34143979 | 2021 | Phase 2 Trial | Cancer Cell | I-SPY2: durvalumab + olaparib + paclitaxel increases pathologic complete response in high-risk HER2-negative breast cancer |
| 35163586 | 2022 | Review | International Journal of Molecular Sciences | Mechanisms, biomarkers and emerging therapies (including PARP inhibitors) for chemotherapy-resistant triple-negative breast cancer |
| 33710534 | 2021 | Review | Targeted Oncology | Overview of PARP inhibitors, including olaparib, approved for BRCA-mutated HER2-negative breast cancer |
| 39520738 | 2024 | Phase 2 Trial | Breast (Edinburgh) | NOBROLA: olaparib monotherapy in HRD-positive, non-germline-BRCA-mutated advanced triple-negative breast cancer |
New Zealand Market Information
Olaparib currently has no marketing authorization on record in New Zealand (0 licenses).
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (PARP inhibitor) — not a conventional cytotoxic chemotherapy agent |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions (no drug-specific toxicity data in current evidence pack; anaemia, neutropenia and thrombocytopenia are class-recognized effects of PARP inhibitors) |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | CBC with differential, renal and hepatic function |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
Please refer to the package insert for safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: The mechanistic rationale (BRCA/HRD-driven synthetic lethality) is strong, and evidence is already at L1 strength — two completed Phase III RCTs (OlympiAD, OlympiA) directly support olaparib's efficacy in BRCA-mutated breast cancer, and it holds approved breast cancer indications elsewhere. However, the drug is not currently marketed in New Zealand, and safety/regulatory data (package insert warnings, contraindications, MOA, DDI) are all outstanding, so guardrails are needed before advancing.
To proceed, the following is needed:
- TFDA/Medsafe package insert (warnings, contraindications) — currently a blocking data gap for safety assessment
- Confirmed mechanism of action data from DrugBank
- BRCA1/2 or HRD biomarker testing pathway/protocol for patient selection
- New Zealand market entry/registration assessment, since olaparib is not currently authorized
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.