FDA Grants Fast Track Designation to IDE161 for Select Pretreated BRCA1/2-Mutated HR+ Breast Cancer

Author(s):

The FDA has granted fast track designation to IDE161 for use in adult patients with advanced or metastatic hormone receptor–positive, HER2-negative breast cancer harboring BRCA1/2 mutations who have progressed after at least 1 hormonal therapy, a CDK4/6 inhibitor, and a PARP inhibitor.

FDA

The FDA has granted fast track designation to IDE161 for use in adult patients with advanced or metastatic hormone receptor–positive, HER2-negative breast cancer harboring BRCA1/2 mutations who have progressed after at least 1 hormonal therapy, a CDK4/6 inhibitor, and a PARP inhibitor.¹

IDE161 is a potent and selective PARG inhibitor.² PARG regulates DNA repair in the same biochemical pathway as PARP, and it is known that PARG inhibition possesses the potential to disrupt the DNA damage repair cycle, which results in cell death. The safety and early efficacy of the agent is under investigation in patients with homologous recombination–deficient (HRD) solid tumors as part of a first-in-human phase 1 trial (NCT05787587).³

Early findings from the dose-escalation portion of the research showed evidence of dose-dependent pharmacodynamic modulation of PAR proteins in the peripheral blood indicative of IDE161 target engagement.⁴ Moreover, preliminary tumor reduction was also observed in several patients, including those with BRCA1/2-mutated endometrial and colon cancers.¹ The data support trial expansion into priority tumor indications, which will include those with HRD-positive associated breast and ovarian cancer, and a basket of other solid tumors.

Earlier this month, the FDA also granted fast track designation to IDE161 for adult patients with advanced or metastatic ovarian cancer with germline or somatic BRCA1/2 mutations who are platinum resistant and have previously received antiangiogenic and PARP inhibitor therapies.⁵

“The US FDA fast track designations for our potential first-in-class PARG inhibitor, IDE161, in both BRCA1/2-mutant breast and ovarian cancers reflect the potential for IDE161 to address the significant unmet medical need in these indications,” Darrin Beaupre, PhD, MD, chief medical officer at IDEAYA Biosciences, stated in a press release.¹ “We are excited that IDE161 has been granted fast track status in 2 separate indications, and we look forward to providing further program updates for IDE161 in the fourth quarter of this year.”

To participate on the trial, patients needed to be at least 18 years of age and have advanced or metastatic solid tumors with documented evidence of genetic HRD alterations.³ Other key inclusion criteria included disease progression on at least 1 prior line of standard-of-care (SOC) therapy in the advanced or metastatic setting, or documented intolerance to SOC treatment. For the expansion portion of phase 1, patients with breast cancer will be required to have estrogen receptor–positive/HER2-negative disease and HRD positivity.

Those with primary central nervous system tumors are not permitted. Other exclusion criteria include impairment of gastrointestinal (GI) function or GI disease that could affect the absorption of IDE161; active, uncontrolled infection; and clinically significant cardiac abnormalities.

Patients could not have undergone major surgery within 4 weeks of enrollment, received radiation within 2 weeks prior to enrollment, received systemic cytotoxic chemotherapy within 4 weeks of enrollment, undergone radioimmunotherapy within 6 weeks of enrollment, received a therapeutic antibody within 4 weeks of enrollment, or received an anticancer small molecule within 5 half-lives or 2 weeks of treatment.

During the dose-escalation phase, patients are being treated with varying doses of oral IDE161 once daily. The primary end points of the research include dose-limiting toxicities, treatment-emergent toxicities, and laboratory abnormalities. In the dose-expansion phase, overall response rate (ORR) serves as a primary end point. ORR during dose escalation and pharmacokinetics are secondary end points.

Investigators continue to evaluate the optimal dose to examine in the phase 2 expansion.¹