A study led by the VHIO Experimental Therapeutics Group in collaboration with the Hereditary Cancer Genetics Group and the Medical Oncology Service of the Vall d’Hebron University Hospital, shows that the selective PARP1 inhibitor saruparib (AZD5305) produces a more potent and lasting antitumor response than olaparib, a first-generation inhibitor currently approved for clinical use, in models derived from patients with alterations in the BRCA1/2 DNA repair pathway.
“As it is a highly selective inhibitor of PARP1, less toxicity is expected and it can be easily combined with chemotherapy or other targeted treatments.” explains Dr. Violeta Serra, head of the Experimental Therapeutics Group at VHIO who led this study, published in the journal Genome Medicine.
The new drug is already being tested in a phase 1/2a clinical trial.
This new and selective PARP1 inhibitor is already being evaluated in patients in the phase 1/2a PETRA clinical trial, in which the Vall d’Hebron University Hospital is participating with the help of Dr. Judith Balmaña, oncologist in the breast cancer unit and head of the Hereditary Cancer Genetics Group at VHIO. The aim of this trial is to determine whether treatment with saruparib, as monotherapy or in combination with other drugs, is safe, tolerable and has antitumor activity in patients with advanced solid tumors that present alterations in the DNA repair pathway through BRCA1/2.
Use of PARP inhibitors in tumors with alterations in DNA repair pathways
Cells exhibit several DNA damage repair pathways, with the BRCA1/2 pathway being one of the most important. Tumours with alterations in the BRCA1 or BRCA2 genes are unable to correctly repair double-stranded DNA damage and are therefore very sensitive to treatments that induce this type of damage, such as platinum-based chemotherapy or PARP inhibitors.
First-generation PARP inhibitors, which inhibit both PARP1 and PARP2, have been shown to be effective in tumors with alterations in this DNA repair pathway, leading to their approval and clinical use in various tumor types where mutations in the BRCA1/2 genes are prevalent, such as breast, ovarian, pancreatic or prostate cancer.
“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 Dr. Violeta 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 selective PARP1 inhibitors are being developed, such as saruparib, studied in this work. It is expected that selective PARP1 inhibition will lead to a more potent and safe response and will facilitate the combination of this type of drugs with others, whether chemotherapy or other targeted therapies.”.
The objective of the research team was to characterize the antitumor activity of saruparib in preclinical models derived from patients and compare it with the activity of the first-generation PARP1/2 inhibitor olaparib.
More powerful and long-lasting response
For this purpose, 13 tumor models were used, derived from patients with breast, ovarian and pancreatic cancer with genetic alterations in the DNA repair pathway through BRCA1/2, who were treated with saruparib as monotherapy or in combination with other targeted therapies (ATR inhibitors) or platinum-based chemotherapy. The antitumor activity was compared with that observed with olaparib, also studying the differences in the mechanism of action and the appearance of resistance between both drugs.
““Saruparib showed superior antitumor activity to the first-generation PARP inhibitor olaparib, with a complete response rate of 75% versus 37%,” explains Dr. Andrea Herencia, postdoctoral researcher in the Experimental Therapeutics Group and first author of the study. “We observed a progression-free survival, which indicates the time elapsed from the start of treatment until the tumor grows again (progression), of more than 386 days in the group of tumors treated with saruparib, compared to 90 days in the group treated with olaparib, which implies a significant difference between both treatments.””.
Taken together, these results demonstrate that the novel PARP1-selective inhibitor saruparib produces a potent anti-tumour response in patient-derived models with DNA damage repair impairments as monotherapy or in combination with other drugs. This study supports the use of selective PARP1 inhibitors in the clinic as a new therapeutic option, and is, in fact, already being tested in patients in the PETRA clinical trial.
This research has been possible thanks to funding from the FERO Foundation through the GHD-Pink Program and the Orozco Family. Dr. Violeta Serra’s laboratory also has the support of the Catalan agency AGAUR, PERIS and the Carlos III Health Institute.
