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 an oral PARP1/2 inhibitor whose established use, per the clinical trial evidence in this pack, is maintenance therapy for platinum-sensitive, BRCA1/2-mutated ovarian, fallopian tube, and peritoneal cancer. The TxGNN model additionally flags Female Breast Carcinoma as a high-confidence indication, and this direction is already strongly corroborated by real-world evidence — 50 clinical trials and 20 publications, including two pivotal completed Phase 3 RCTs (OlympiAD, OlympiA).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the regulatory license data (0 licenses on file); per trial-derived evidence (NCT05078671), historically used for maintenance treatment of platinum-sensitive, BRCA-mutated advanced ovarian/fallopian tube/peritoneal cancer |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.09% |
| Evidence Level | L1 |
| US Market Status | ✗ Not Marketed |
| Number of NDAs | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
A formal mechanism-of-action record is not yet populated in the regulatory database (data gap, see below). However, the evidence pack’s repurposing rationale and multiple trial descriptions consistently characterize olaparib as a PARP1/2 inhibitor that exploits synthetic lethality: in tumor cells carrying BRCA1/2 pathogenic mutations (homologous recombination deficiency, HRD), PARP inhibition blocks base-excision repair of single-strand DNA breaks, causing replication fork collapse and selective death of BRCA-deficient cells while sparing normal cells.
The original evidence base for this mechanism was built in BRCA-mutated ovarian cancer, but BRCA1/2 mutations and HRD are shared molecular features across ovarian and breast tumors — both are gynecologic/hormone-pathway malignancies with substantial overlap in hereditary cancer syndromes (hereditary breast and ovarian cancer, HBOC). This shared biology is why the same synthetic-lethality mechanism translates directly to breast cancer.
This is not a purely theoretical extrapolation: it is already backed by two completed Phase 3 RCTs specific to breast cancer — OlympiAD (metastatic, germline BRCA-mutated, HER2-negative breast cancer) and OlympiA (adjuvant, high-risk early breast cancer) — both demonstrating significant efficacy benefit. The clinical population, however, remains restricted to patients with confirmed germline (or in some studies somatic) BRCA1/2 mutations or broader HRD status, not unselected breast cancer patients.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT05078671 | Phase 4 | Recruiting | 160 | Post-marketing PK-boosting study to improve olaparib exposure, tolerability, and cost-effectiveness across approved indications including BRCA-mutated breast cancer |
| NCT04421963 | Phase 3 | Active, not recruiting | 185 | Rollover study providing continued olaparib access/long-term safety data for patients benefiting from prior oncology trials |
| NCT02418624 | Phase 1/2 | Completed | 25 | Carboplatin-olaparib followed by olaparib monotherapy vs. capecitabine as first-line therapy in BRCA1/2-mutated, HER2-negative advanced breast cancer |
| NCT04683679 | Phase 2 | Recruiting | 34 | Pembrolizumab + ablative radiotherapy ± olaparib in metastatic triple-negative/HR+/HER2- breast cancer |
| NCT02624973 | Phase 2 | Active, not recruiting | 200 | PETREMAC personalized-medicine platform trial in high-risk breast cancer, with olaparib as one treatment arm |
| NCT06201234 | Phase 2 | Recruiting | 176 | Olaparib + elacestrant vs. olaparib alone in HR+/HER2- advanced breast cancer with gBRCA1/2 mutations |
| NCT05498155 | Phase 2 | Active, not recruiting | 50 | Neoadjuvant olaparib monotherapy vs. olaparib + durvalumab in BRCA-mutated, early-stage HER2-negative breast cancer |
| NCT04330040 | Phase 4 | Completed | 202 | Real-world Indian cohort of olaparib in gBRCA1/2-mutated metastatic breast cancer and platinum-sensitive relapsed ovarian cancer |
| NCT01445418 | Phase 1 | Completed | 103 | AZD2281 (olaparib) + carboplatin in BRCA1/2-mutated familial and sporadic triple-negative breast/ovarian cancer |
| NCT00679783 | Phase 2 | Completed | 99 | AZD2281 (olaparib) response rate and correlative biomarkers in known-BRCA and triple-negative breast cancer, plus ovarian carcinoma |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 34081848 | 2021 | RCT | NEJM | OlympiA primary results: adjuvant olaparib significantly reduces recurrence in BRCA1/2-mutated early breast cancer |
| 28578601 | 2017 | RCT | NEJM | OlympiAD primary results: olaparib shows antitumor activity in metastatic breast cancer with germline BRCA mutation |
| 36228963 | 2022 | RCT | Annals of Oncology | OlympiA overall survival analysis confirming sustained benefit of adjuvant olaparib in high-risk early breast cancer |
| 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 long-term safety and OS trend favoring olaparib |
| 33119476 | 2020 | Phase 2 Cohort | J Clin Oncol | TBCRC 048: olaparib response extends beyond germline BRCA1/2 to somatic and other HRR gene mutation carriers |
| 34143979 | 2021 | Phase 2 Cohort | Cancer Cell | I-SPY2: durvalumab + olaparib + paclitaxel increases pathologic complete response in HER2-negative breast cancer |
| 39520738 | 2024 | Phase 2 | Breast (Edinburgh) | NOBROLA: olaparib monotherapy effective in HRD-positive triple-negative breast cancer without germline BRCA1/2 mutation |
| 38112922 | 2024 | Real-world | Breast Cancer Res Treat | LUCY final analysis: real-world effectiveness and safety of olaparib consistent with OlympiAD trial data |
| 33710534 | 2021 | Review | Targeted Oncology | Overview of PARP inhibitors (olaparib, talazoparib) approved for gBRCA-mutated, HER2-negative breast cancer |
US Market Information
No market authorizations are currently on file — the regulatory record shows 0 licenses and a “Not Marketed” status for this drug entity in this dataset.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (PARP inhibitor; synthetic-lethality mechanism, not conventional cytotoxic chemotherapy) |
| 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 warnings and precautions |
| 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: Evidence level L1 is met with two completed Phase 3 RCTs (OlympiAD, OlympiA) plus consistent real-world confirmation (LUCY), strongly supporting olaparib’s efficacy in breast cancer — but strictly within the biomarker-defined population (germline/somatic BRCA1/2-mutated or HRD-positive), not all breast cancer patients. Formal safety labeling and MOA documentation are still missing, which blocks a full go decision.
To proceed, the following is needed:
- TFDA/FDA package insert warnings, contraindications, and DDI data (currently a blocking data gap — DG001)
- Formal MOA documentation from DrugBank (DG002)
- Confirmation of BRCA1/2 germline mutation or HRD testing as a mandatory patient-selection gate before any indication expansion
- Regulatory pathway assessment given the current “Not Marketed” status and zero licenses on file
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.