Introduction:

Standard treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy (ADT) plus systemic androgen receptor pathway inhibitors (ARPIs), taxanes, radiopharmaceuticals, or targeted therapies. Despite these treatment options, disease progression is inevitable. Treatments that improve upon the outcomes with current treatment options are urgently needed.

B7-H3, a type I transmembrane protein, is overexpressed in prostate cancer and associated with poor prognosis and unresponsiveness to certain treatments. Ifinatamab deruxtecan (I-DXd; MK-2400/DS-7300a) is a B7-H3-directed antibody-drug-conjugate, with a plasma-stable tetrapeptide-based cleavable linker and the potent topoisomerase I inhibitor payload DXd. In preclinical models, I-DXd exerted potent antitumor activity in B7-H3-expressing tumors and acceptable pharmacokinetics and safety. Preliminary results from the first-in-human phase 1/2 IDeate-PanTumor01 study of I-DXd demonstrated antitumor activity and manageable safety in multiple solid tumors, including heavily pretreated mCRPC.

Methods:

IDeate-Prostate01 (NCT06925737) is a phase 3, randomized, open-label study (Figure). Eligible participants must have: histologically or cytologically confirmed mCRPC; documented prostate-specific antigen (PSA) or radiologic disease progression; and have received 1 or 2 previous ARPIs. Approximately 1,440 participants will be randomized 1:1 to I-DXd or docetaxel (~720 participants per treatment arm). Randomization will be stratified by metastatic site (liver versus bone-only versus other), geographic region (Region 1 [Australia, European Union, Israel, Japan, South Korea, Switzerland, United Kingdom, and United States of America] versus rest of the world), B7-H3 expression (high versus low versus unevaluable), and prior prostate-specific membrane antigen-targeted radionuclide therapy (yes versus no). Dual primary endpoints are overall survival and radiographic progression-free survival. Secondary endpoints include time to first subsequent therapy, objective response, duration of response, time to pain progression, time to PSA progression, PSA response, time to first symptomatic skeletal-related event, and safety and tolerability. Recruitment is ongoing.

Results:

Conclusion:

Funding: Funding for this study was provided by Daiichi Sankyo Company, Limited and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA