Talzenna (talazoparib)

P1/2, N=90, Recruiting, St. Jude Children's Research Hospital | Active, not recruiting --> Recruiting | N=46 --> 90

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.

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.

Talazoparib switches from Type-II PARPi behavior in PARP1A762 to allosteric, pro-retention Type-I behavior for PARP1V762. Thus, both PARPi efficacy and dose-limiting tolerability depends on PARP1 allele, motivating variant-guided cancer therapies.

The single covariate effect of baseline creatinine clearance on CLt0/Ft showed that relative to the reference value for normal renal function, CLt0/Ft decreased by 8% for mild, 27% for moderate, and 46.7% for severe renal impairment. Simulations showed that a dose reduction of enzalutamide does not require talazoparib dose modification since the magnitude of exposure reduction for talazoparib was not considered clinically significant.

Additionally, combining BMN673 with radiotherapy exerted a synergistic anticancer effect on ATM-deficient CRC cells, which was prevented by autophagy inhibition. The findings identified the ATF4-GDF15 pathway as a crucial mediator of BMN673 sensitivity in ATM-deficient CRC cells, revealing therapeutic vulnerability beyond canonical DNA damage repair pathways and providing new insight for combination therapy strategies.

P=N/A, N=600, Not yet recruiting, Pfizer | Trial completion date: Oct 2026 --> Nov 2028 | Trial primary completion date: Oct 2026 --> Nov 2028

Scramble LNCaP, BRCA1 KO, and BRCA2 KO cells were treated with the PARPi talazoparib, the DNA-PK inhibitor nedisertib and their combination. Therapeutically targeting NHEJ presents a promising approach in treating BRCA-mutated PCa. Further in vivo investigations are required to assess the tolerability of this drug combination.

Promising results have led to the approval of several PARPi agents as monotherapy or in combination with ARPIs in selected or unselected patients when chemotherapy is not clinically indicated. However, some questions remain regarding patient selection and treatment sequencing.

To identify the most suitable PARPi for UC, we compared Olaparib with Talazoparib. In conclusion, we suggest Talazoparib treatment of UC to be highly efficacious on all models examined when combined with PLX51107. This new combination treatment allows efficient application of PARPi Talazoparib to all UC patients, independent of Cisplatin pretreatment and genetic BRCAness.

P2, N=35, Active, not recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Oct 2026 --> Oct 2027 | Trial primary completion date: Oct 2025 --> Oct 2026