olaparib

Overview

Olaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor used as a targeted anticancer therapy. It inhibits PARP1 and related PARP-mediated DNA repair processes, thereby exploiting defects in homologous recombination repair (HRR) pathways and increasing tumor cell sensitivity to DNA damage. Clinically, olaparib has been developed as a maintenance and combination therapy in several malignancies, especially tumors with homologous recombination deficiency, including ovarian cancer and prostate cancer.

Its therapeutic significance lies in synthetic lethality: cancer cells with impaired DNA repair are more dependent on PARP-mediated repair, so PARP inhibition can preferentially impair tumor survival. Recent research has continued to evaluate olaparib both as a single agent and in combination with other therapies such as abiraterone, durvalumab, carboplatin/paclitaxel, and experimental DNA repair–targeting compounds. These studies reinforce its role as a central agent in DNA damage response–directed oncology.

Focus of Latest Publications

Recent publications have focused on olaparib across both translational and clinical settings, with emphasis on efficacy, resistance, companion diagnostics, and combination strategies.

Several studies addressed clinical implementation and patient selection. A multicenter Japanese study on high-risk HER2-negative early breast cancer emphasized that timely germline BRCA testing is essential as a companion diagnostic for adjuvant olaparib. In ovarian cancer, a retrospective study identified severe anemia as a risk factor in Japanese patients receiving olaparib, reinforcing the importance of toxicity monitoring during maintenance therapy. Another clinical study examined long-term and short-term responders to maintenance olaparib in primary and recurrent epithelial ovarian carcinoma, aiming to characterize clinical and molecular determinants of response.

Olaparib was also evaluated in prostate cancer. A phase II study tested olaparib plus durvalumab in an HRR-unselected metastatic castration-resistant prostate cancer population, while another single-arm phase II trial investigated olaparib combined with abiraterone in HRR-mutated metastatic hormone-sensitive prostate cancer. In both contexts, olaparib was studied as part of combination regimens intended to extend DNA damage vulnerability and improve disease control. A separate prostate cancer study showed that olaparib treatment induced M1C in HR-competent castration-resistant cells, linking exposure to transcriptional changes associated with LINE-1 regulation.

In endometrial cancer, the DUO-E study and related exploratory analyses evaluated durvalumab with carboplatin/paclitaxel followed by durvalumab with or without olaparib maintenance. The plain-language summary described olaparib as part of a targeted therapy strategy in newly diagnosed advanced or recurrent disease, and exploratory biomarker analyses noted progression-free survival benefit in the overall trial framework. These findings place olaparib within a broader immunotherapy-plus-chemotherapy maintenance paradigm.

A major theme across the recent literature is drug resistance and sensitization. In ovarian cancer, one study reported that P-gp/ABCB1 influences resistance to paclitaxel and olaparib, highlighting an efflux-mediated resistance mechanism. In Ewing sarcoma, autophagy was found to impair sensitivity to PARP inhibitors, and the clinical evaluation noted that olaparib failed to produce substantial responses, suggesting an unresolved resistance mechanism. In triple-negative breast cancer, RNF146 enhanced olaparib sensitivity by downregulating XRCC5, and this translated into reduced tumor growth and increased apoptosis in vivo. Another study on USP1 inhibitors reported synergistic antitumor activity with olaparib in triple-negative breast cancer, supporting the concept that additional DNA repair inhibition can potentiate PARP inhibition.

Multiple studies explored combination strategies that intensify DNA damage or impair repair. RU486 combined with olaparib enhanced apoptosis in endometriosis by targeting hormonal signaling and DNA repair simultaneously. In colorectal cancer, FASN inhibition synergized with irinotecan and was further potentiated by olaparib as maintenance treatment. A small molecule disrupting G4-STAT1 interaction showed synergy with olaparib in colon cancer cell death by increasing DNA damage and disrupting repair pathways. In neuroblastoma, electroporation-based approaches were used to improve chemotherapy efficacy while also exploring whether olaparib-mediated inhibition of DNA repair could potentiate treatment effects. In nasopharyngeal carcinoma, SLC44A4 overexpression increased sensitivity to several DNA-damaging agents, including olaparib, cisplatin, doxorubicin, temozolomide, and etoposide.

Olaparib also served as a reference or comparator in drug development studies. A medicinal chemistry study on dual PARP-1/EGFR inhibitors compared new compounds against olaparib and erlotinib, showing stronger dual inhibition for one candidate. Another study developed a PARP1-specific Pt(II)-based targeted drug conjugate for ovarian cancer and reported higher tumor growth inhibition than cisplatin, olaparib, and their physical mixture in SKOV3 mouse xenograft models, with lower toxicity. Similarly, an in vitro glioblastoma study examined an olaparib-cyanine dye conjugate designed to improve delivery, and a fragment-based drug design study used olaparib as a reference ligand in PARP-1 modeling.

Resistance and pharmacology were also examined at the molecular and formulation level. A 2026 pharmacology study used physiologically based pharmacokinetic modeling to assess bridging between adult and pediatric olaparib formulations, emphasizing the role of intrasubject variability and the question of whether a clinical trial is needed for a non-bioequivalent batch. Another study on ovarian cancer resistance mechanisms identified novel PARP inhibitor resistance pathways and again implicated P-gp/ABCB1 in olaparib resistance. These findings underscore the importance of transporter biology, formulation behavior, and exposure-response relationships in olaparib development.

Across tumor types, olaparib continues to be investigated as a DNA repair-targeting backbone therapy. It is being combined with carboplatin, taxanes, abiraterone, durvalumab, RU486, irinotecan, and other agents; used in biomarker-driven settings such as BRCA-mutated or HRR-mutated disease; and studied in preclinical models including MDA-MB-231, MDA-MB-436, SK-OV-3, 4T1 cells, human hepatocellular carcinoma cell lines, and NMRI mice. Collectively, these studies reinforce olaparib’s central role in exploiting DNA repair vulnerabilities while also documenting the biological and clinical barriers that limit response.

Key Publications

• NEWJul Is a Clinical Trial With a Non-Bioequivalent Batch Necessary? The Critical Role of Intrasubject Variability in Olaparib Formulation Bridging by PBPK. (Clinical pharmacology and therapeutics, 2026, PMID 41979227): "...using the bridging of adult and pediatric olaparib formulations as an example."
• NEWJul Identification of novel drug-specific PARP inhibitor resistance mechanisms in ovarian cancer-implications for clinical practice. (British journal of cancer, 2026, PMID 41998207): "We have shown that P-gp/ABCB1 influences resistance to paclitaxel and olaparib, but similar niraparib resistance mechanisms have not been described [2, 3]."
• Jul Real-world uptake of gBRCA testing as a companion diagnostic for olaparib in patients with high-risk HER2-negative early breast cancer in Japan: a cross-sectional multicenter study (BRCAwareness). (Breast cancer (Tokyo, Japan), 2026, PMID 42176176): "Timely gBRCA testing as a companion diagnostic for adjuvant olaparib is essential."
• Jun Downregulation of SLC44A4 in nasopharyngeal carcinoma is associated with malignant progression, B-cell/TLS-related immune features, and sensitivity to DNA-damaging agents. (PloS one, 2026, PMID 42361082): "SLC44A4 overexpression also increased sensitivity to DNA-damaging agents, including temozolomide, doxorubicin, cisplatin, olaparib, and etoposide, while decreasing sensitivity to 5-fluorouracil."
• Jun Electroporation as a strategy to improve the efficacy of chemotherapy in neuroblastoma: an in vitro study. (Radiology and oncology, 2026, PMID 42359758): "...explored whether inhibition of DNA repair mechanisms with olaparib potentiates its effects."
• Jun RNF146 enhances olaparib sensitivity in triple-negative breast cancer via XRCC5 downregulation. (Biochemical and biophysical research communications, 2026, PMID 41932112): "RNF146 overexpression markedly enhanced olaparib sensitivity in vitro and significantly inhibited tumor growth while promoting apoptosis in vivo."
• Jun Synergistic RU486 and olaparib therapy enhances apoptosis in endometriosis by simultaneously targeting hormonal signalling and DNA repair. (British journal of pharmacology, 2026, PMID 41707660): "This study aimed to evaluate the synergistic therapeutic efficacy of combining RU486 with the PARP inhibitor olaparib, focusing on reactivating p53-dependent apoptosis in endometriotic lesions."
• Jun Molecular Boomerangs Against Cancer: Design, Synthesis, Biological Evaluation, and In Silico Study of Novel Dual PARP-1/EGFR Inhibitors. (Drug development research, 2026, PMID 42207930): "Compared with the reference medications erlotinib and olaparib, compound 3h showed the highest dual inhibition (EGFR IC50 = 1.62 μM and PARP-1 IC50 = 0.36 μM) in enzymatic experiments, demonstrating that these compounds effectively inhibited both EGFR and PARP-1."
• May Autophagy impairs the sensitivity of Ewing sarcoma cells to PARP inhibitors. (Cancer chemotherapy and pharmacology, 2026, PMID 42215796): "In clinical evaluation, however, the PARPi olaparib failed to elicit substantial responses, suggesting an unknown mechanism of resistance to PARPi in Ewing sarcoma."
• May FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response. (Cancer research, 2026, PMID 41661672): "Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment."