Olaparib
| 證據等級: L5 | 預測適應症: 1 個 |
目錄
Olaparib: From BRCA-Mutated Ovarian Cancer to Female Breast Carcinoma
One-Sentence Summary
Olaparib is a PARP (poly-ADP ribose polymerase) inhibitor originally developed for maintenance treatment of platinum-sensitive, BRCA-mutated relapsed ovarian, fallopian tube, or peritoneal cancer. The TxGNN model predicts it may also be effective for Female Breast Carcinoma, and this direction is already supported by 50 clinical trials and 20 publications, including multiple completed Phase 3 randomized controlled trials (OlympiAD, OlympiA).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | BRCA-mutated, platinum-sensitive relapsed ovarian cancer (maintenance therapy) — extracted from clinical trial context (NCT05078671); no formal TFDA/BfArM label text available |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.09% |
| Evidence Level | L1 |
| Germany Market Status | 未上市 (Not currently marketed) |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Olaparib is a PARP1/2 inhibitor. In tumors with BRCA1/2 mutations (germline or somatic, resulting in homologous recombination repair — HRR — deficiency), it works through synthetic lethality: PARP inhibition blocks base-excision repair of single-strand DNA breaks, and in HRR-deficient cells the resulting unrepaired double-strand breaks cannot be fixed, selectively killing cancer cells while sparing normal HRR-competent cells.
Ovarian cancer and breast cancer share substantial molecular biology overlap — both are frequently driven by germline BRCA1/2 mutations as part of hereditary breast and ovarian cancer (HBOC) syndrome. Since the synthetic lethality mechanism depends on the tumor's BRCA/HRR status rather than tissue of origin, a drug validated in BRCA-mutated ovarian cancer is mechanistically well-positioned to work in BRCA-mutated breast cancer as well.
This is not merely a theoretical extrapolation: the TxGNN prediction is corroborated by an extensive body of completed Phase 3 evidence (OlympiAD, OlympiA) demonstrating that olaparib improves progression-free and overall survival in both metastatic and early-stage BRCA-mutated, HER2-negative breast cancer. This substantially strengthens confidence in the model's prediction beyond a purely computational signal.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT05078671 | Phase 4 | Recruiting | 160 | Pharmacokinetic boosting study to improve olaparib exposure, tolerability, and cost-effectiveness in patients already using it for BRCA-mutated breast/ovarian cancer — reflects routine post-marketing clinical use. |
| NCT04421963 | Phase 3 | Active, not recruiting | 185 | Rollover study allowing patients who completed prior olaparib oncology trials (including breast cancer) to continue treatment, indicating durable long-term clinical benefit. |
| NCT02418624 | Phase 1/2 | Completed | 25 | Carboplatin-olaparib sequencing vs. capecitabine as first-line therapy in BRCA1/2-mutated, HER2-negative advanced breast cancer. |
| NCT02624973 | Phase 2 | Active, not recruiting | 200 | PETREMAC trial — personalized treatment of high-risk breast cancer, evaluating predictive/prognostic biomarkers for olaparib response. |
| NCT05564377 | Phase 2 | Recruiting | 2900 | ComboMATCH — large genomically-guided basket trial with an olaparib treatment arm for solid tumors including breast cancer. |
| NCT03470805 | Phase 2 | Completed | 9 | Olaparib maintenance after response to trabectedin-liposomal doxorubicin in recurrent BRCA-related carcinoma. |
| NCT04683679 | Phase 2 | Recruiting | 34 | Pembrolizumab + ablative radiotherapy ± olaparib in metastatic triple-negative/HR-positive, HER2-negative breast cancer. |
| NCT07321015 | Phase 2 | Not yet recruiting | 72 | Maintenance fluzoparib (another PARP inhibitor) in platinum-sensitive advanced TNBC with/without BRCA1/2 mutation — indirect class-effect support. |
| NCT06545942 | Phase 1 | Active, not recruiting | 220 | MOMA-313 monotherapy or combined with a PARP inhibitor (incl. olaparib) in HRR-deficient advanced/metastatic solid tumors. |
| NCT05700669 | Phase 1b/2 | Completed | 3 | AsiDNA™ combined with olaparib in recurrent ovarian, breast, and prostate cancer previously progressed on PARP inhibitor therapy. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36228963 | 2022 | RCT | Annals of Oncology | Overall survival results from the OlympiA Phase 3 trial of adjuvant olaparib in germline BRCA1/2-mutated, high-risk early breast cancer. |
| 34081848 | 2021 | RCT | New England Journal of Medicine | OlympiA trial: adjuvant olaparib reduces recurrence in BRCA1/2-mutated early breast cancer. |
| 28578601 | 2017 | RCT | New England Journal of Medicine | OlympiAD: olaparib shows antitumor activity in metastatic breast cancer with germline BRCA mutation. |
| 30689707 | 2019 | RCT | Annals of Oncology | OlympiAD final overall survival and tolerability: olaparib vs. chemotherapy of physician's choice in gBRCA-mutated HER2-negative metastatic breast cancer. |
| 36893711 | 2023 | RCT | European Journal of Cancer | OlympiAD extended follow-up confirming survival and safety findings for olaparib in gBRCA-mutated metastatic breast cancer. |
| 33119476 | 2020 | RCT (Phase II) | Journal of Clinical Oncology | TBCRC 048: olaparib activity in metastatic breast cancer with somatic BRCA1/2 or other HRR-gene mutations beyond germline BRCA. |
| 34143979 | 2021 | RCT (Phase II) | Cancer Cell | I-SPY2 trial: durvalumab + olaparib + paclitaxel increases pathologic complete response in high-risk HER2-negative breast cancer. |
| 35163586 | 2022 | Review | International Journal of Molecular Sciences | Molecular mechanisms 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/investigated for BRCA-mutated breast cancer. |
| 37253112 | 2023 | Translational/Basic Science | Cancer Research | Functional characterization of RAD51C variants relevant to HRR-deficiency and PARP inhibitor sensitivity in breast/ovarian cancer. |
Germany Market Information
Olaparib currently has no marketing authorization records on file for this evidence pack (market status: 未上市 / not marketed; total authorizations: 0). No product name, dosage form, or approved indication text is available at this time.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (PARP inhibitor) — acts via synthetic lethality in HRR-deficient tumor cells rather than as a conventional broad-spectrum cytotoxic agent |
| Myelosuppression Risk | Medium — anemia is the most frequently reported hematologic toxicity across olaparib trials (e.g., OlympiAD, OlympiA); neutropenia and thrombocytopenia occur less commonly but warrant monitoring |
| Emetogenicity Classification | Low to Moderate — nausea is commonly reported with oral PARP inhibitors but is generally manageable and not classified as highly emetogenic |
| Monitoring Items | Complete blood count (hemoglobin, neutrophils, platelets) at baseline and periodically during treatment; renal function; long-term surveillance for myelodysplastic syndrome/acute myeloid leukemia (a recognized class-related risk with prolonged PARP inhibitor exposure) |
| Handling Protection | Given the genotoxic/mutagenic potential associated with PARP inhibitors, handling per institutional hazardous drug protocols is advisable even though olaparib is administered orally |
Safety Considerations
Please refer to the package insert for safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: The evidence level is L1, supported by multiple completed Phase 3 RCTs (OlympiAD, OlympiA) directly demonstrating olaparib's efficacy in BRCA-mutated breast cancer, and the mechanistic rationale (BRCA/HRR-driven synthetic lethality) is well established. However, formal Taiwan/Germany regulatory data (marketing authorization, package insert warnings, contraindications, and DDI profile) are currently unavailable, so guardrails are required before any deployment or clinical decision-making.
To proceed, the following is needed:
- TFDA/BfArM package insert warnings, precautions, and contraindications (currently a Blocking data gap, DG001)
- Formal DrugBank-sourced mechanism of action documentation (currently a High-severity data gap, DG002)
- Drug-drug interaction (DDI) data specific to local formulary (current query status: not found)
- Confirmation of local (Taiwan/Germany) marketing authorization status before considering repurposing pathway
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.