Olaparib
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
Olaparib: From BRCA-Mutated Ovarian Cancer to Female Breast Carcinoma
One-Sentence Summary
Olaparib is an oral PARP1/2 inhibitor originally used as maintenance therapy for 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, with 50 clinical trials and 20 publications currently supporting this direction — including two completed Phase 3 RCTs (OlympiA, OlympiAD).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Maintenance treatment of platinum-sensitive relapsed, BRCA-mutated ovarian/fallopian tube/peritoneal cancer (derived from trial-level drug description in the evidence pack; not present in the regulatory license dataset) |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.09% |
| Evidence Level | L1 |
| EU Market Status | Not marketed (per this dataset — see caveat below) |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed MOA data is not populated in the drug record (original_moa: [Data Gap]), but the mechanism is well documented in the supporting literature within this evidence pack. Olaparib inhibits poly(ADP-ribose) polymerase (PARP1/2), blocking base-excision repair of single-strand DNA breaks. In cells with a dysfunctional homologous recombination pathway — most notably those carrying germline or somatic BRCA1/2 mutations — this creates a state of “synthetic lethality,” causing accumulation of unrepaired DNA damage and selective tumor cell death (PMID 26344419).
BRCA1/2 mutations are the shared genetic driver of hereditary breast-ovarian cancer syndrome, so the biological rationale for extending Olaparib from ovarian cancer into BRCA-mutated breast cancer is direct rather than speculative. This is reflected in the internal rationale note for this candidate: “乳癌中 BRCA1/2 生殖系突變族群機轉明確，已為監管機關核准適應症” — i.e., olaparib’s use in germline BRCA-mutated breast cancer is mechanistically well established and already regulator-approved in multiple markets internationally (via OlympiA for adjuvant early breast cancer and OlympiAD for metastatic breast cancer).
Regulatory caveat: the same rationale note flags that this dataset’s “Not marketed / 0 authorizations” status for this jurisdiction may reflect a regional data gap rather than a true absence of approval (“此資料集標記Not marketed可能為地區性差異”). This discrepancy should be verified against the primary regulatory source before any downstream decision is finalized.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01445418 | Phase 1 | Completed | 103 | Olaparib (AZD2281) + carboplatin in BRCA1/2-mutated breast/ovarian cancer and sporadic TNBC/ovarian cancer; dose-finding |
| NCT06201234 | Phase 2 | Recruiting | 176 | Randomized: elacestrant + olaparib vs. olaparib alone in HR+/HER2− BRCA1/2-mutated advanced breast cancer |
| NCT05498155 | Phase 2 | Active, not recruiting | 50 | Neoadjuvant olaparib monotherapy vs. olaparib + durvalumab in BRCA-mutated, early-stage HER2− breast cancer |
| NCT00679783 | Phase 2 | Completed | 99 | Non-randomized study of AZD2281 in known BRCA or recurrent breast/ovarian cancer; objective response rate |
| NCT02624973 | Phase 2 | Active, not recruiting | 200 | PETREMAC — personalized primary medical treatment for high-risk mammary cancer, incl. PARP-inhibitor arm |
| NCT02418624 | Phase 1 | Completed | 25 | Carboplatin-olaparib vs. capecitabine as first-line treatment in BRCA1/2-mutated, HER2− advanced breast cancer |
| NCT03109080 | Phase 1 | Completed | 24 | Olaparib + radiation therapy in inflammatory/locoregionally advanced/metastatic TNBC |
| NCT05358639 | Phase 1 | Active, not recruiting | 36 | Olaparib + navitoclax (Bcl-2/Bcl-XL inhibitor) in BRCA1/2/PALB2-mutated TNBC and recurrent HGSC |
| NCT05209529 | Phase 2 | Withdrawn | 0 | Neoadjuvant olaparib ± durvalumab in BRCA-associated TNBC (pathological complete response endpoint) |
| NCT04417192 | Phase 2 | Completed | 30 | Preoperative olaparib monotherapy vs. olaparib + pembrolizumab in HRD-positive gynecologic/breast malignancy setting |
(50 trials total were retrieved for this indication; the 10 most directly relevant to breast cancer are shown above.)
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 34081848 | 2021 | RCT | N Engl J Med | OlympiA: adjuvant olaparib significantly improves invasive disease-free survival in germline BRCA1/2-mutated, HER2− early breast cancer |
| 36228963 | 2022 | RCT | Ann Oncol | OlympiA overall survival analysis confirms sustained benefit of adjuvant olaparib in high-risk early breast cancer |
| 28578601 | 2017 | RCT | N Engl J Med | OlympiAD: olaparib monotherapy shows antitumor activity in germline BRCA-mutated metastatic breast cancer |
| 30689707 | 2019 | RCT | Ann Oncol | OlympiAD final OS results: olaparib vs. chemotherapy of physician’s choice in gBRCA/HER2− metastatic breast cancer |
| 36893711 | 2023 | RCT | Eur J Cancer | OlympiAD extended follow-up confirms OS and safety profile of olaparib in gBRCA metastatic breast cancer |
| 33119476 | 2020 | RCT | J Clin Oncol | TBCRC 048: olaparib activity in metastatic breast cancer with somatic BRCA or non-BRCA HRR gene mutations |
| 38588696 | 2024 | RCT | Nature | PARTNER trial: neoadjuvant olaparib + chemotherapy in germline BRCA wild-type triple-negative breast cancer |
| 34143979 | 2021 | RCT | Cancer Cell | I-SPY2: durvalumab + olaparib + paclitaxel increases pathologic complete response in HER2− stage II/III breast cancer |
| 33710534 | 2021 | Review | Targeted Oncology | Overview of PARP inhibitors (olaparib, talazoparib) approved for gBRCA-mutated, HER2− breast cancer |
| 25366685 | 2015 | Phase 1 | J Clin Oncol | Olaparib monotherapy activity across the spectrum of BRCA1/2-associated cancers, including breast cancer |
(20 publications total were retrieved for this indication; the 10 highest-tier items are shown above.)
EU Market Information
No marketing authorization records are present for Olaparib in this dataset (0 licenses on file). Given that Olaparib (Lynparza®) is a globally established PARP inhibitor with two completed Phase 3 RCTs supporting breast cancer use (OlympiA, OlympiAD), this is very likely a data completeness gap in the regulatory dataset rather than a true absence of market authorization — as also flagged in the model’s own rationale text. This should be independently verified against the primary regulator/SmPC source before finalizing any decision.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy — PARP1/2 inhibitor acting via synthetic lethality in homologous-recombination-deficient (e.g., BRCA1/2-mutated) tumor cells; not a conventional cytotoxic chemotherapy agent |
| Myelosuppression Risk | Please refer to the SmPC warnings and precautions (no drug-specific hematologic toxicity data provided in this evidence pack) |
| Emetogenicity Classification | Please refer to the SmPC warnings and precautions |
| Monitoring Items | Please refer to the SmPC warnings and precautions |
| Handling Protection | Please refer to the SmPC warnings and precautions |
Safety Considerations
Please refer to the SmPC for safety information.
Note: this evidence pack flags a Blocking-severity data gap (DG001) for TFDA-equivalent label warnings/contraindications, and a High-severity gap (DG002) for mechanism-of-action documentation. Neither can currently be sourced from DrugBank/regulatory data in this pack.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Two completed Phase 3 RCTs (OlympiA for adjuvant early breast cancer, OlympiAD for metastatic breast cancer) plus a broad supporting body of Phase 1–2 trials and reviews give this candidate L1-level evidence — the mechanistic link (BRCA1/2-driven synthetic lethality) is strong and well precedented. However, the regulatory record in this dataset (0 authorizations, “not marketed”) and the missing safety/MOA fields are unresolved and must be closed before this indication can move past guardrailed review.
To proceed, the following is needed:
- TFDA/EU label warnings and contraindications (DG001 — Blocking; currently prevents S1 safety screening)
- Confirmed DrugBank mechanism-of-action record (DG002 — High)
- Reconciliation of the “Not marketed / 0 licenses” status against actual EU marketing authorization records for Lynparza®/olaparib
- A jurisdiction-specific safety monitoring plan (hematologic toxicity, renal function) informed by the SmPC once retrieved
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.