Study design of OMAHA-015: A phase 2 basket study of steroidogenesis inhibitor opevesostat in participants with selected solid tumors.

TPS3183 Background: Opevesostat (MK-5684; ODM-208), an oral steroidogenesis inhibitor, selectively inhibits CYP11A1, blocking synthesis of all steroid hormones and their precursors, and may suppress steroid-driven tumor growth. The randomized, open-label, phase 2 OMAHA-015 trial (NCT06979596) is designed to evaluate the efficacy and safety of opevesostat compared with standard of care in breast, ovarian, and endometrial cancers. Methods: Cohort A will enroll participants (pts) with locally advanced unresectable or metastatic hormone receptor–positive (estrogen receptor and/or progesterone receptor ≥1% expression)/HER2-negative breast cancer (IHC 0, 1+ or 2+/ISH-) and disease progression on or after ≥1 prior endocrine-based therapy in the metastatic setting. Exclusion criteria include any line of cytotoxic chemotherapy (chemo) or PARP inhibitor in the inoperable or noncurative advanced/metastatic setting and prior treatment with both fulvestrant and exemestane in the metastatic setting. Cohort B will enroll pts with platinum-sensitive, histologically confirmed high-grade epithelial ovarian (including high-grade serous or predominantly serous, high-grade endometrioid, clear cell, or malignant mixed Müllerian tumors [carcinosarcoma]), fallopian tube, or primary peritoneal carcinomas. Pts must have received 4-8 cycles of platinum-based doublet chemo in a third-line setting for ovarian cancer with ≤9 weeks between the last dose of third-line chemo and randomization. Cohort C will enroll pts with histologically confirmed primary advanced or recurrent low-grade endometrioid carcinoma (FIGO grade 1/2, or well/moderately differentiated), with known pMMR status, and wild type p53 expression. Pts must either be treatment naive or have received 1 prior line of platinum-based therapy in the advanced/metastatic or adjuvant/neoadjuvant setting. In cohort A, ~80 pts will be randomized 1:1 to arm 1: opevesostat 5 mg PO twice daily (BID) + daily corticosteroids or arm 2: physician’s decision of fulvestrant 500 mg IM (D1 and D15 of cycle 1 and D1 of each cycle thereafter) or exemestane 25 mg PO daily. Randomization will be stratified by 1 line versus ≥2 lines of prior endocrine therapy. In cohort B, ~90 pts will be randomized 1:1 to arm 3: opevesostat 5 mg PO BID + daily corticosteroids; or arm 4: observation. In cohort C, ~80 pts will be randomized 1:1 to arm 5: opevesostat 5 mg PO BID + daily corticosteroids; or arm 6: physician’s choice of megestrol acetate 80 mg PO BID, alternating megestrol + tamoxifen 20 mg PO BID, or letrozole 2.5 mg PO daily. The primary end point is progression-free survival per RECIST v1.1 assessed by blinded independent central review (BICR). Secondary end points include overall survival, clinical benefit rate (cohort A only), objective response rate, and duration of response per RECIST v1.1 assessed by BICR, and safety. The study is currently enrolling. Clinical trial information: NCT06979596 .