Rubraca (rucaparib)

These collective findings suggest the potential of immunotherapy for CRPC in overcoming resistance barriers and improving patient outcomes, with bispecific T cell engagers (Xaluritamig, 59% PSA50) and PSMA-directed CAR-T therapy (P-PSMA-101, >50% PSA reduction) emerging as the most promising near-term candidates and biomarker-stratified combinations (nivolumab plus rucaparib, 84.6% PSA50, in HRR-deficient patients) illustrating the transformative power of precision patient selection; however, these findings require validation in larger, biomarker-stratified trials before definitive conclusions can be drawn. Translating this potential into clinical reality requires optimized patient selection through predictive biomarkers and rigorously validated Phase III trials to confirm durable clinical responses and long-term survival benefits.

hMOB2 depletion sensitized A549 cells to olaparib and rucaparib, resulting in a marked reduction in long-term clonogenic survival. Sensitization required functional p53, as it was absent in p53-null cells but restored upon p53 re-expression. These findings suggest that hMOB2 contributes to PARP inhibitor responses in lung cancer cells and underscore the complexity of PARP inhibitor sensitivity beyond classical HR deficiency.

P2, N=79, Completed, University of Colorado, Denver | Active, not recruiting --> Completed | Trial completion date: Dec 2026 --> Feb 2026

P2, N=30, Completed, Medical College of Wisconsin | Active, not recruiting --> Completed

Collectively, VEGF-, PARP-, and FRα-targeted therapies have enabled more rational treatment sequencing, informed combination strategies, and personalized clinical decision-making in ovarian cancer. Ongoing efforts to define optimal sequencing, overcome acquired resistance, and refine predictive biomarkers are expected to further enhance the durability and breadth of benefit from targeted therapies and advance precision oncology in gynecologic malignancies.

P2, N=79, Active, not recruiting, University of Colorado, Denver | Trial completion date: Dec 2025 --> Dec 2026

P1/2, N=25, Terminated, University of Michigan Rogel Cancer Center | Trial completion date: Jun 2028 --> May 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2025 --> May 2025; Due to financial hardships suffered by the stakeholder

P3, N=61, Active, not recruiting, Alliance for Clinical Trials in Oncology | Trial primary completion date: Mar 2026 --> Mar 2027

To enable organelle-specific modulation of PARP activity, we synthesized a series of trialkyl(aryl)phosphonium conjugates of olaparib and rucaparib designed to target mitochondria by cardiolipin binding. Phosphonium conjugation preserves PARP1 inhibitory activity while conferring mitochondrial targeting and enhanced anticancer potency. These findings support the development of mitochondria-targeted PARP inhibitors as a next-generation therapeutic strategy with the potential to improve efficacy and overcome resistance in HR-deficient tumors.

In recurrent ovarian cancer, niraparib+pembrolizumab showed modest activity with durable responses in homologous recombination-deficient (HRD) tumors; olaparib+durvalumab demonstrated high activity in gBRCA platinum-sensitive relapse, and adding bevacizumab broadened benefit in non-BRCA cohorts. In the newly diagnosed disease, rucaparib+nivolumab maintenance failed to improve PFS versus rucaparib alone. Endometrial trials (olaparib+durvalumab; talazoparib+avelumab in mismatch repair-proficient disease) showed limited activity overall, with signals restricted to biomarker-selected subgroups...PARP+PD-1/PD-L1 combinations are most compelling in ovarian cancer, particularly in BRCA/HRD tumors and, in selected settings, with the addition of bevacizumab, while frontline maintenance benefit remains unproven and endometrial activity is modest. Biomarker-guided selection, rational triplets with non-cytotoxic partners, and optimized sequencing warrant further evaluation.

Interrogation of PARPi response within biological pathways identified through gene set enrichment analysis (GSEA) revealed significant changes to proteins involved in Epithelial-Mesenchymal Transition (EMT), E2F targets, and cholesterol homeostasis. Our study establishes proteomic evidence supporting the poly-pharmacological characteristics of Niraparib, Olaparib, and Rucaparib in HGSOC cells.

Clinically, PARP inhibitors (PARPi), such as olaparib, niraparib, rucaparib, and talazoparib, exploit synthetic lethality in homologous recombination-deficient tumors and are increasingly applied in ovarian, breast, prostate, and pancreatic cancers. By integrating canonical DNA repair roles with non-canonical signaling and host-virus interactions, PARPs represent pivotal regulators. Similarly, the versatile therapeutics of PARPi have implications that extend beyond oncology into a broader and diverse range of other human diseases.