Rubraca (rucaparib)

Targeted agents did not demonstrate a significant clinical benefit in mesothelioma treatment, nevertheless a small group of patients might harbor potentially actionable somatic mutations, as in homologous repair recombination genes. In this paper we report two cases of patients with heavily pretreated pleural mesothelioma that had a relevant clinical benefit with rucaparib treatment based on somatic BRCA 1 and BRCA 2 mutations detected through next generation sequencing.

The FDA has approved four PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) for the treatment of ovarian, breast, prostate, and pancreatic cancer...The Chinese NMPA has approved three PARP antagonists (fuzuloparib, pamiparib, senaparib) for the treatment of ovarian cancer. All seven of these drugs are orally bioavailable and fall within the criteria of Lipinski's rule of five. Drug resistance develops in most PARP-inhibitor-treated cancer patients within one or two years.

Afterwards, the cytostatic and cytotoxic responses of these models to three targeted anti-PARP therapies, Olaparib, Rucaparib and Niraparib, were analyzed, revealing their sensitivity. These results demonstrated that our liquid overlay-based technique provides both a large cell culture panel, whatever the tissue type or pathological level, and an automated drug screening process that could lead to highly predictive efficacy results.

P2, N=130, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | Suspended --> Terminated; Bankruptcy of partner: Clovis

Some of the most prominent examples are Olaparib (IC50 = 5 nM), Rucaparib (IC50 = 7 nM), and Talazoparib (IC50 = 1 nM), which were optimized with docking scores between -9.0 to -9.3 kcal/mol and validated by in vitro and in vivo assays, achieving 60-80% inhibition of tumor growth in BRCA-mutated models and achieving up to 21-month improvement in progression-free survival in clinical trials of BRCA-mutated breast and ovarian cancer patients. Employing computation and experimental verification in a hybrid strategy have brought next-generation inhibitors to the clinic with accelerated development, higher efficacy, and personalized treatment for breast cancer patients. Future approaches, including AI-aided generative models and multi-omics integration, have the promise to further refine inhibitor design, paving the way for precision oncology.

PARPi efficacy depends strongly on BRCA and HRD status. Olaparib-based regimens provide the greatest clinical benefit with acceptable safety in BRCA+ and HRD+ disease, whereas PARPi appear to be of limited value in HRD-negative ovarian cancer.

ER10 values for talazoparib, olaparib rucaparib, ABT888 and niraparib were 1.5, 1.8, 2.8, 1.4, and 1.4, respectively. When the p21 gene was knocked down, both the decrease in mitochondrial membrane potential and senescence level were attenuated, suggesting that p21 is involved in senescence induction after γ-irradiation combined with talazoparib treatment. Taken together, we showed that PARP inhibitor talazoparib treatment in combination with γ-irradiation causes cellular senescence in lung cancer cells, involving p21 function.

This optimized dosing schedule successfully established the MTD for RUB with nal-IRI and 5-FU, overcoming prior challenges with PARP inhibitor and irinotecan combinations. The promising ORR and DCR support further evaluation of this regimen in advanced GI malignancies.

P2, N=20, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Completed --> Active, not recruiting | Trial completion date: Jun 2025 --> Nov 2026 | Trial primary completion date: Jun 2025 --> Nov 2026

While this survey is meant as hypotheses-generating, PrMN represent a rare but clinically relevant complication, particularly uncommon when PARPi are administered as first-line therapy. Their occurrence does not appear to be associated with the specific PARPi used or with BRCA mutation status. Early detection, monitoring, and identification of predictive factors are crucial as ovarian cancer outcomes improve and treatment exposure increases.

Copa/R had a favorable safety profile with a signal of efficacy supporting future studies of PARPi with PI3Ki.

BRCA2 germline-mutated patients obtained significantly greater benefit from olaparib compared to BRCA1-mutated patients. PFS benefit from niraparib (primary or recurrent setting) is comparable to clinical trials. There was no difference in benefit between niraparib and rucaparib in the recurrent setting.