Lynparza (olaparib)

P2, N=36, Not yet recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Initiation date: Mar 2024 --> Sep 2024

We show that TRIM33 knockdown sensitizes MM cells to the PARP inhibitor Olaparib, and this is synergistic with the standard of care therapy bortezomib, even in co-culture with bone marrow stromal cells (BMSCs). These findings suggest that TRIM33 loss contributes to the pathogenesis of high-risk MM and that this may be therapeutically exploited through the use of PARP inhibitors.

However, optimal identification of high-risk patients who may derive benefit from this genomically-directed therapy is debated. In this study, we sought to characterize the real-world proportion of gBRCA1/2 PV carriers eligible for adjuvant olaparib according to the OlympiA criteria, and to compare clinicopathologic characteristics and outcomes between eligible and ineligible patients.

Upregulation of intracellular NAD+ levels by the addition of nicotinamide also induced resistance to olaparib and talazoparib in C1 cells. Taken together, our findings suggest that upregulation of intracellular NAD+ is one of the factors underlying the acquisition of PARP inhibitor resistance.

P2, N=550, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P2, N=298, Active, not recruiting, AstraZeneca | Trial completion date: Jun 2023 --> Dec 2024

We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.

Here, we review the newly approved PARPi plus ARSI treatments within the context of the mCRPC treatment landscape, provide an overview of practical considerations for the combinations in clinical practice, highlight the importance of HRR testing, and discuss the benefits of treatment intensification for patients with mCRPC.

In this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.

The HR activity of xenograft tumor tissues quantitatively correlated with the effect of olaparib. Our data suggest that ASHRA could be a useful assay for diagnosing HBOC and predicting the efficacy of PARP inhibitors.

P2, N=122, Active, not recruiting, National Cancer Institute (NCI) | Terminated --> Active, not recruiting | Trial completion date: Jun 2022 --> Apr 2025

P2, N=288, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2024 --> Dec 2024 | Trial primary completion date: Apr 2024 --> Dec 2024

P1, N=102, Completed, CSPC Ouyi Pharmaceutical Co., Ltd.

P1/2, N=220, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=30, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

Olaparib is not a cost-effective maintenance treatment option. Companion diagnostics are an equally important cost driver as the drug itself.

Inflammation-related blood data, such as neutrophil count, obtained at the initial pre-treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer.

Olaparib plus abiraterone has a manageable and predictable safety profile.

P2, N=8, Active, not recruiting, John Diaz | Recruiting --> Active, not recruiting | N=48 --> 8

Two CDK-inhibitors (CDKi), the broad range dinaciclib and the CDK12-specific SR-4835, strongly reduced the expression of key HR genes and impaired HR functionality, as illustrated by BRCA1 and RAD51 nuclear foci obliteration. However, no olaparib response improvement was observed in vivo with SR-4835. These data support that the implementation of CDK-inhibitors could be effective to sensitize TNBC to olaparib as well as possibly to cisplatin or gemcitabine.

P1, N=18, Suspended, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

Following the approval of olaparib for the treatment of BRCA1/2 mutated, castration-resistant prostate cancer, further targeted therapeutic approaches are currently under development. In our review article, we provide an overview of current molecular testing in prostate cancer and discuss possible consequences.

P3, N=174, Active, not recruiting, The Netherlands Cancer Institute | Trial completion date: Dec 2029 --> Dec 2033 | Trial primary completion date: Apr 2024 --> Oct 2024

P1/2, N=152, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Not yet recruiting --> Recruiting

P2, N=122, Terminated, National Cancer Institute (NCI) | Active, not recruiting --> Terminated; Inadequate accrual rate

P2, N=36, Active, not recruiting, University of Washington | Trial completion date: Mar 2025 --> Apr 2024

P1, N=176, Recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd.

Our case underscores the potential clinical utility of olaparib in germline ATM-mutated gastric cancer and emphasizes the need for further exploration through larger clinical trials. Ongoing research and clinical trials are essential for optimizing the use of PARP inhibitors, identifying biomarkers, and advancing personalized treatment strategies for gastric cancer.

Furthermore, functional experiments demonstrated that silencing CARD11 and GATA2 impairs HR repair efficiency and enhances the sensitivity of tumor cells to olaparib treatment. In summary, in the absence of mutations in the HR genes, the sensitivity of tumor cells to PARP inhibitors and platinum-based chemotherapy may be enhanced in a subset of breast cancer patients with LNGC somatic mutations.

γ-H2AX can be characterized as a predictive biomarker for poorer patient survival. Consequently, upcoming clinical trials focused on the efficacy of targeted therapies influencing the DNA repair system and radiotherapy should evaluate γ-H2AX as a potential biomarker for therapy response. Furthermore, γ-H2AX may serve as a viable target for treatment in the future.

P1, N=140, Recruiting, Hoffmann-La Roche | Trial completion date: Feb 2025 --> Jun 2027 | Trial primary completion date: Jun 2024 --> Jun 2026

Besides, the impact of compounds 3a-e and 4b on the activity of PARP-1 was investigated, where 3c, 3d, and 3e demonstrated comparable efficiencies to olaparib...In addition, a significant inhibition of cell proliferation and a remarkable 15 to 50-fold reduction in the number of colonies compared to the control group were recorded. Finally, the PARP-1 inhibitory potential of the novel hybrids was compared to the co-crystal of the target receptor (PDB ID: 6NTU) using molecular docking.

P=N/A, N=3000, Not yet recruiting, AstraZeneca

P1, N=24, Terminated, Haihe Biopharma Co., Ltd. | N=350 --> 24 | Recruiting --> Terminated; Business decision

Moreover, in xenograft models, CRABP2 knockdown significantly suppressed tumorigenesis and enhanced Olaparib sensitivity, with the effect being reversed upon Caspase-8 knockdown. These findings suggest that CRABP2 may modulate Olaparib sensitivity in ovarian cancer through the Caspase-8/ROS axis, highlighting its potential as a target for Olaparib sensitization.

P2, N=90, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2023 --> Jan 2025 | Trial primary completion date: Dec 2023 --> Jan 2025

P2, N=63, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

Importantly, compound 16 demonstrates superior antitumor potency compared to the PARP1 inhibitor Olaparib and the c-Met inhibitor Crizotinib, either alone or in combination, in MDA-MB-231 and HCT116OR xenograft models. These findings highlight the potential of PARP1/c-Met dual inhibitors for expanding the indications of PARP1 inhibitors and overcoming tumor cells' resistance to them.

PARPi switch maintenance to consolidate a response to platinum-based therapy is recommended for earlier treatment lines to have the greatest impact on the chance of cure and length of survival. This article reviews the clinical utility of PARPis and how to integrate them into best practices.

In a large real-world sample, more men with eBC are at clinical high risk according to the inclusion criteria of monarchE, NATALEE and OlympiA than would be expected in women. This is most likely due to more advanced stages at initial diagnosis in men. To evaluate whether CDK4/6 and PARP inhibitors improve prognosis also in men should be the topic of future real- world analyses.

P1, N=6, Not yet recruiting, Mary D Chamberlin | Initiation date: Feb 2024 --> May 2024

The SeqOne assay offers a clinically validated approach to detect HRD.