Lynparza (olaparib)

Our findings highlight the side effects of Olaparib therapy in terms of haematology which could be avoided. Further studies are needed to better understand the therapeutic management of Olaparib and the mitigation of haematologic complications.

Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

P1, N=117, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2024 --> Mar 2025

P1, N=42, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Nov 2025

Our study highlights the crucial function of cGAS signaling in mediating PARPi resistance in ovarian cancer cells. These findings provide valuable novel therapeutic strategies targeting cGAS to improve the efficacy of PARPi-based treatments for ovarian cancer.

P2, N=401, Active, not recruiting, AstraZeneca | Trial completion date: Sep 2024 --> Sep 2025

P2, N=20, Active, not recruiting, Yuan Yuan | Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2026 --> Oct 2024

With the tremendous success of the PARP inhibitor olaparib in clinical practice, synthetic lethality has become an important field for the discovery and development of anticancer drugs...Currently, many drug candidates that were designed and developed on the basis of the concept of synthetic lethality have entered clinical trials. Taking representative synthetic lethal targets Poly ADP-ribose polymerase 1 (PARP1), Werner syndrome helicase (WRN) and protein arginine methyltransferase 5 (PRMT5) as examples, this article briefly discusses the application and research progress of synthetic lethality in the development of anticancer drugs.

P2, N=31, Active, not recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Phase classification: P2a --> P2

P2, N=390, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

Results suggest that TALA + ENZA may provide improvements in clinical outcomes relative to OLAP + AAP and NIRA + AAP in 1 L mCRPC; however, inherent limitations associated with the complexity of the analyses must be considered.

No abstract available

PARPi are active against PCa with HRR mutations, especially in those with germline or somatic BRCA1/2 mutations.  There is still a need to further optimize patient stratification strategies, particularly for combination approaches. Future research should focus on refining predictive biomarkers, improving treatment delivery strategies, and exploring the potential benefits of PARPi in earlier stages of the disease.

P2, N=4, Completed, National Cancer Institute (NCI) | Recruiting --> Completed | N=25 --> 4 | Trial completion date: Dec 2026 --> Feb 2024

P1/2, N=13, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | N=26 --> 13 | Trial completion date: Oct 2023 --> Apr 2024 | Recruiting --> Terminated | Trial primary completion date: Oct 2023 --> Apr 2024; Treatment availability issue: The manufacturer of AsiDNA™ decided to cease production to develop an improved version, and the contract ensuring access to this molecule has expired.

P2, N=147, Completed, ARCAGY/ GINECO GROUP | Active, not recruiting --> Completed

P2, N=130, Completed, Italian Sarcoma Group | Active, not recruiting --> Completed

The combined effects of elevated NADP+ levels and olaparib synergistically suppress tumor cell growth. Overall, our study offers a promising strategy for the clinical application of NADP+.

In conclusion, the findings of the present study demonstrated that AZD2281 significantly enhanced FABP4 expression, leading to diminished antitumor efficacy in OC cells with a BRCA mutation by regulating CEBPα-PPARγ. Conversely, the combination of AZD2281 and FABP4 inhibitor BM S309403 demonstrated heightened antitumor effectiveness, presenting a promising therapeutic strategy for treating patients with OC with a BRCA mutation.

P3, N=554, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris

P1/2, N=133, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2024 --> Apr 2025 | Trial primary completion date: Nov 2024 --> Apr 2025

The results demonstrate that the iRGD-DOX-oHA-PLNs efficiently downregulated single and double-strand DNA repair proteins and enhanced DNA damage while decreasing PD-L1 expression compared to olaparib. Accordingly, iRGD-DOX-oHA-PLN treatment showed significantly higher efficiency in reducing levels of primary tumor growth and numbers of metastases to the lung and liver compared to olaparib in vitro and in vivo in both BRCA1-mutant and wild type TNBC orthotopic xenograft models.

BRCA testing in PC still presents several difficulties in clinical practice that can limit access to PARPi treatment. Better implementation of molecular testing to identify BRCA-mutated patients is crucial for tailored treatment in mCRPC.

Targeted panel sequencing in olaparib-sensitive models lacking BRCA1/2 alterations revealed a MUS81 variant as a possible mechanism underlying PARPi sensitivity. Combined, we show that ex vivo RAD51 analysis effectively predicts in vivo olaparib response and revealed a subset of PARPi-sensitive, HR-deficient ovarian cancer PDX models, lacking a BRCA1/2 alteration.

MARCHF3 has emerged as a pivotal regulator of the immune landscape in the HCC TME and is a potent predictive biomarker for HCC. Combining interventions targeting the DNA damage response with ICIs is a promising treatment strategy for HCC.

This was associated with increased resistance to Cisplatin and Olaparib and reduced DNA damage and apoptosis in response to these agents. These data demonstrate for the first time that MPZL3 acts as an adhesion molecule and that MPZL3 loss results in EMT, decreased proliferation, and drug resistance in ovarian cancer. Our study suggests that decreased MPZL3 expression is a phenotype of ovarian cancer tumor progression and metastasis and may contribute to treatment failure in advanced-stage patients.

While the exact mechanisms determining the nature of the PARPis and AZD8797 interaction remain to be uncovered, our data indicate that, in a subset of models, selected PARPis strongly synergize with the inhibition of CX3CR1, suggesting a potential therapeutic opportunity.

UWB-OlaJR exhibits varying sensitivity to PARPis, showing cross-resistance to veliparib and talazoparib, and sensitivity with increased cytotoxicity to niraparib and rucaparib. Moreover, S1 nuclease fiber assay shows that niraparib and rucaparib induce greater DNA single-strand gaps than other PARPis, leading to increased DNA damage and cell death. Our study provides novel insights into differential PARPi sensitivity in olaparib-resistant BRCA-mutant OvCa, which requires further investigation of inter-agent differences in large prospective studies.

Furthermore, the use of poly-adenosine diphosphate-ribose polymerase inhibitors in patients with hereditary GC is considered safe and effective. This study provides substantial evidence for guiding the establishment of early treatment for patients with advanced-stage/metastatic GC who harbored BRCA1/2 mutations.

In a real-world setting, PARP inhibitors showed efficacy comparable to that reported in published randomized controlled trials and had acceptable safety profiles.

LCP1 could be a potential therapeutic target for patients with OC who are resistant to olaparib. Our study provides a new mechanism of olaparib resistance.

Dato-DXd is active in breast cancer models. Dato-DXd has TROP2 dependent and independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.

P=N/A, N=981, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Sep 2025 | Trial primary completion date: Dec 2025 --> Sep 2025

The observed results could prompt further investigation.

ADMET analysis was applied to determine the pharmacokinetic properties of the tested compounds. The applied theoretical approach showed that the biomedical activity of the investigated coumarins is comparable to the inhibitory activity and pharmacokinetic properties of Olaparib, already used in the PDAC treatment.

P1, N=6, Recruiting, Mary D Chamberlin | Not yet recruiting --> Recruiting

P3, N=805, Active, not recruiting, AstraZeneca | Trial completion date: Aug 2027 --> Apr 2027

P3, N=174, Active, not recruiting, The Netherlands Cancer Institute | Trial primary completion date: Oct 2024 --> Jul 2025

We developed a novel mathematical framework accounting for intrinsic resistance to olaparib, identified by fitting the model to tumour growth metrics from breast cancer patient-derived xenograft (PDX) data...High WEE1 expression was also linked to resistance, highlighting an opportunity for combining PARP and WEE1 inhibitors. This framework facilitates a fully automated way of capturing intrinsic resistance, and accounts for the pharmacological response variability captured within PDX studies and hence provides a precision medicine approach.

Olaparib-resistant xenografts were treated with olaparib, ATR inhibitor (ATRi, ceralasertib), CHK1 inhibitor (CHK1i, MK-8776) or their combinations. Our collective findings indicate that ATR/CHK1 pathway inhibition restores the olaparib efficacy in resistant BRCA1/2MUT high-grade serous OC, highlighting promising approach for olaparib rechallenge of non-responsive patients. Uncovered mechanisms might improve our understanding of acquisition and overcoming resistance to olaparib in ovarian cancer.

P1, N=30, Recruiting, AstraZeneca | Trial completion date: Oct 2024 --> Dec 2025 | Trial primary completion date: Oct 2024 --> Dec 2025

P2, N=40, Completed, Roswell Park Cancer Institute | Active, not recruiting --> Completed