The purpose of the study is to evaluate the progression-free survival (PFS) of casdatifan versus placebo when each is given in combination with cabozantinib in adult patients with confirmed advanced or metastatic clear cell Renal Cell Carcinoma who have experienced progression on or after prior anti-PD-1 or anti-PD-L1 immunotherapy.

Inclusion Criteria:

• Unresectable and measurable locally advanced or metastatic renal cell carcinoma with a primary clear cell component.
• A Karnofsky Performance Status (KPS) score ≥ 80%
• At least 1 target lesion measurable by computed tomography/magnetic resonance imaging per RECIST 1.1, not within a field of prior radiation therapy.
• Adequate organ and marrow function, ≤ 1 week prior to randomization.
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test.

Exclusion Criteria:

• Received prior treatment with a HIF-2α inhibitor or cabozantinib.
• Other prior malignancy active within the previous year except for locally curable cancers that have been apparently cured.
• Ongoing clinically significant toxicities related to any prior anticancer treatment, or toxicities Grade ≥ 3 per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) regardless of relatedness to prior anticancer therapies.
• Uncontrolled or poorly controlled hypertension, defined as a sustained blood pressure > 150 mmHg systolic or > 90 mmHg diastolic despite optimal antihypertensive treatment.
• History of leptomeningeal disease or spinal cord compression.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Arcus will provide access to individual de-identified participant data and related study documents (e.g., protocol, Statistical Analysis Plan [SAP], Clinical Study Report [CSR]) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions.