Olaparib
| Evidence Level: L1 | Predicted Indications: 1 |
Table of Contents
Olaparib: From Ovarian Cancer to Female Breast Carcinoma
One-Sentence Summary
Olaparib is a PARP1/2 inhibitor originally used as maintenance therapy for platinum-sensitive, BRCA1/2-mutated relapsed ovarian cancer. The TxGNN model predicts it may also be effective for Female Breast Carcinoma, and this direction is already backed by 50 clinical trials and 20 publications, including two pivotal completed Phase 3 RCTs (OlympiAD, OlympiA) in gBRCA1/2-mutated, HER2-negative breast cancer.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Ovarian cancer (platinum-sensitive relapsed, BRCA1/2-mutated maintenance) — per clinical trial records; no India label on file |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.09% |
| Evidence Level | L1 |
| India Market Status | Not Marketed |
| Number of Registrations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Olaparib is a poly(ADP-ribose) polymerase (PARP1/2) inhibitor. It works by trapping PARP–DNA complexes at sites of single-strand DNA damage, blocking base-excision repair. In tumor cells with homologous recombination deficiency (HRD) — most commonly caused by germline or somatic BRCA1/2 mutations — this creates synthetic lethality, selectively killing cancer cells that cannot repair the resulting double-strand breaks. (Detailed formal MOA documentation from DrugBank is still pending — see DG002 below; the mechanism above is drawn from the trial-level evidence in this pack.)
Ovarian and breast cancer share a substantial biological link: both are classic BRCA1/2-associated malignancies, and patients with germline BRCA1/2 mutations carry elevated lifetime risk for both cancers. Since olaparib’s efficacy in ovarian cancer is driven specifically by HRD/BRCA-mutation status rather than tissue-of-origin, the same synthetic-lethality mechanism plausibly extends to BRCA-mutated breast tumors.
This is not merely theoretical — the evidence pack shows olaparib has already completed pivotal Phase 3 trials in breast cancer (OlympiAD for metastatic disease, OlympiA for adjuvant high-risk early breast cancer), both restricted to germline BRCA1/2-mutated, HER2-negative populations. This strongly corroborates the TxGNN prediction and indicates the “new indication” is mechanistically well-established rather than speculative, even though it is not yet reflected in an India market authorization.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02282020 | Phase 3 | Completed | 266 | Olaparib monotherapy vs. physician’s-choice chemotherapy in gBRCA1/2-mutated, platinum-sensitive relapsed patients after ≥2 prior platinum regimens. Source flags this as high-relevance to the breast cancer evidence base (OlympiAD analog), but the trial title describes an ovarian cancer population — recommend manual verification of indication tagging. |
| NCT06580314 | Phase 3 | Recruiting | 880 | One vs. two years of maintenance olaparib ± bevacizumab in BRCA1/2-mutated or HRD+ ovarian cancer after first-line platinum chemotherapy. |
| NCT04330040 | Phase 4 | Completed | 202 | Real-world Phase 4 study in Indian patients with platinum-sensitive relapsed ovarian cancer and gBRCA1/2-mutated metastatic breast cancer — directly relevant to the India market context. |
| NCT05498155 | Phase 2 | Active, not recruiting | 50 | Neoadjuvant olaparib monotherapy vs. olaparib + durvalumab in BRCA-mutated, early-stage HER2-negative breast cancer. |
| NCT02418624 | Phase 1 | Completed | 25 | Carboplatin + olaparib followed by olaparib maintenance vs. capecitabine as first-line therapy in BRCA1/2-mutated, HER2-negative advanced breast cancer. |
| NCT01445418 | Phase 1 | Completed | 103 | Dose-finding of olaparib + carboplatin in BRCA1/2 carriers with breast and ovarian cancer, including sporadic triple-negative breast cancer. |
| NCT01237067 | Phase 1 | Completed | 77 | PK/PD study of olaparib + carboplatin in refractory/recurrent breast, ovarian, uterine, and cervical cancers. |
| NCT04553926 | N/A | Completed | 661 | Real-world post-marketing surveillance of Lynparza (olaparib) tablets across approved indications in South Korea. |
| NCT02264678 | Phase 1/2 | Active, not recruiting | 357 | Modular study of ceralasertib (ATR inhibitor) combined with chemotherapy and/or olaparib in advanced solid malignancies; supportive safety/PK data. |
| NCT05932862 | Phase 1 | Recruiting | 429 | First-in-human study of XL309 (ISM3091) alone or combined with olaparib in advanced solid tumors. |
40 additional trials were identified but are lower priority (early-phase combination studies, terminated/withdrawn, or non-breast-specific populations).
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 34081848 | 2021 | RCT | N Engl J Med | OlympiA: adjuvant olaparib significantly improved invasive disease-free survival in gBRCA1/2-mutated, HER2-negative high-risk early breast cancer. |
| 28578601 | 2017 | RCT | N Engl J Med | OlympiAD: olaparib improved progression-free survival vs. chemotherapy in gBRCA-mutated, HER2-negative metastatic breast cancer. |
| 36228963 | 2022 | RCT | Ann Oncol | OlympiA overall survival update: adjuvant olaparib confirmed an OS benefit in high-risk early breast cancer. |
| 36893711 | 2023 | RCT | Eur J Cancer | OlympiAD extended follow-up: median OS 19.3 vs. 17.1 months for olaparib vs. chemotherapy (not statistically significant); safety profile consistent. |
| 30689707 | 2019 | RCT | Ann Oncol | OlympiAD final OS/tolerability results — favorable tolerability profile vs. chemotherapy. |
| 33119476 | 2020 | RCT | J Clin Oncol | TBCRC 048: olaparib shows activity in metastatic breast cancer with somatic BRCA1/2 or other HR-pathway gene mutations, beyond germline BRCA. |
| 34143979 | 2021 | RCT | Cancer Cell | I-SPY2: durvalumab + olaparib + paclitaxel increased pathologic complete response rates vs. paclitaxel alone in high-risk HER2-negative breast cancer. |
| 38588696 | 2024 | RCT | Nature | PARTNER trial: neoadjuvant olaparib added to carboplatin-paclitaxel evaluated in BRCA-wildtype triple-negative breast cancer (n=559). |
| 33710534 | 2021 | Review | Target Oncol | Overview of PARP inhibitors (olaparib, talazoparib) approved for gBRCA-mutated, HER2-negative breast cancer. |
| 31650727 | 2020 | Review | Ann Lab Med | Review of treatment and prevention strategies for BRCA1/2 pathogenic-variant breast cancer, including the role of PARP inhibitors. |
10 additional publications (mechanistic/functional variant-classification studies) support the BRCA/HRD rationale but are secondary to the clinical evidence above.
India Market Information
Olaparib currently has no market authorization on file in India (market status: Not Marketed; 0 registrations). No product/license records are available to summarize.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (PARP inhibitor; synthetic lethality in HRD/BRCA-mutated tumors) |
| 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
Drug Interactions: 444 documented interactions on file. Notable Major-severity interactions include Aprepitant, Dexamethasone, and Clarithromycin. Multiple Moderate-severity interactions are also documented, including Metformin, Bupropion, Cimetidine, Miconazole, Ondansetron, Rosuvastatin, and Simvastatin.
Key warnings and contraindications are not yet available in this evidence pack — please refer to the package insert once available.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Evidence strength is high (L1) — two completed pivotal Phase 3 RCTs (OlympiAD, OlympiA) already establish olaparib’s efficacy in gBRCA1/2-mutated, HER2-negative breast cancer, reinforced by an India-specific real-world Phase 4 study (NCT04330040). However, olaparib has no current India market authorization and two blocking/high-severity data gaps remain open, so guardrails are needed before advancing.
To proceed, the following is needed:
- India-specific label warnings/contraindications (DG001, Blocking — source: TFDA-equivalent regulator, PDF label parsing)
- Formal mechanism-of-action documentation via DrugBank API (DG002, High)
- Confirmation of India registration/licensing pathway status
- Verification that the indication population is restricted to germline BRCA1/2-mutated, HER2-negative breast cancer (consistent with the approved global label), including confirmation of the NCT02282020 population mismatch noted above
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.