A study carried out by the Experimental Therapeutics Group of the Vall d’Hebron Institute of Oncology (VHIO), in collaboration with the Hereditary Cancer Genetics Group and the Medical Oncology Service of the Vall d’Hebron University Hospital, has shown that the selective PARP1 inhibitor saruparib (AZD5305) generates a stronger and more prolonged antitumor response than olaparib, a first-generation inhibitor already approved for clinical use, in models derived from patients with alterations in the DNA repair pathway through BRCA1/2.
Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved to treat breast, ovarian, pancreatic, and prostate cancers with homologous recombination repair (HRR) deficiencies. Because PARP1 inhibition alone is sufficient to cause synthetic lethality in homologous recombination-deficient (HRD) tumors, PARPi are being developed to target cancers. developing selective PARP1 inhibitorssuch as saruparib (AZD5305). In fact, experts hope that selective inhibition of PARP1 will offer an improved safety profile, which would allow its combination with other DNA damage repair inhibitors.
In This studypublished in the journal Genome Medicine, the aim was to evaluate the antitumor activity of AZD5305 in preclinical models derived from patients and compare it with that of the first-generation PARP1/2 inhibitor, olaparib, as well as to identify resistance mechanisms. “As it is a highly selective PARP1 inhibitor, less toxicity is expected and it can be easily combined with chemotherapy or other targeted treatments,” explains Violeta Serra, head of the Experimental Therapeutics Group at VHIO, who led this study.
Phase 1/2A clinical trial
This innovative and selective PARP1 inhibitor is already being evaluated in patients through the phase 1/2a PETRA clinical trial, in which the Vall d’Hebron University Hospital is participating under the direction of Judith Balmaña, oncologist in the breast cancer unit and head of the Hereditary Cancer Genetics Group at VHIO. The objective of this trial is to determine whether treatment with saruparib, either as monotherapy or in combination with other drugs, is effective in treating patients with PARP1 deficiency. safe, tolerable and shows antitumor activity in patients with advanced solid tumors that present alterations in the BRCA1/2-mediated DNA repair pathway.
Cells have several pathways to repair DNA damage, including: the BRCA1/2 pathway one of the most relevantTumors with alterations in the BRCA1 or BRCA2 genes cannot adequately repair double-strand DNA damage, making them particularly vulnerable to treatments that induce this type of damage, such as platinum-based chemotherapy or PARP inhibitors. In this regard, first-generation PARP inhibitors, which block both PARP1 and PARP2, have been shown to be effective in tumors with alterations in this DNA repair pathway. This led to their approval and clinical use in several types of cancer where mutations in the BRCA1/2 genes are common.
Violeta Serra, head of the Experimental Therapeutics Group at VHIO (left) and Andrea Herencia, postdoctoral researcher of the Experimental Therapeutics Group (right).
“However, despite the potent initial response to drugs targeting PARP1/2, the emergence of resistance remains a clinical limitation and, therefore, more effective and safer treatments are needed to expand the therapeutic arsenal for these patients,” says Serra. “Since PARP1 inhibition is sufficient to cause lethality in tumors with alterations in BRCA1/2, and PARP2 inhibition is associated with greater hematotoxicity, new generation inhibitors selective for PARP1 are being developed, such as similarstudied in this work,” adds the specialist.
Results of the study
To carry out the study, 13 tumor models derived from patients with breast, ovarian and pancreatic cancer who had genetic alterations in the BRCA1/2-mediated DNA repair pathway were used. These patients were treated with saruparib, either as monotherapy or in combination with other targeted therapies, such as ATR inhibitors, or with platinum-based chemotherapy. The antitumor activity of saruparib was compared with that of olaparibalso evaluating the differences in the mechanisms of action and the emergence of resistance between both drugs.
“Saruparib showed superior antitumor activity to the first-generation PARP inhibitor olaparib, with a complete response rate of 75 percent versus 37 percent,” he explains. Andrea Herencia, postdoctoral researcher of the Experimental Therapeutics Group and first author of the study“We observed a progression-free survival rate, which indicates the time elapsed from the start of treatment until the tumor grows again, of more than 386 days in the group of tumors treated with saruparib, compared with 90 days in the group treated with olaparib, which implies a significant difference between both treatments,” he notes.
These findings show that the novel selective PARP1 inhibitor saruparib generates a potent antitumor response in patient-derived models with DNA repair abnormalities, both as monotherapy and in combination with other treatments.
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