Cancer of Unknown Primary in Transition: From Empirical Chemotherapy to Immunotherapy and Molecularly Guided Treatment

ABSTRACT Cancer of unknown primary (CUP) is a heterogeneous group of metastatic malignancies in which the primary site remains unidentified despite appropriate diagnostic evaluation. Historically, most patients with unfavorable CUP have received empirical platinum‐based chemotherapy, but recent advances in immune checkpoint inhibition, comprehensive genomic profiling (CGP), tissue‐agnostic therapy, and tissue‐of‐origin prediction are changing the treatment landscape. Contemporary management therefore requires integration rather than simple replacement of empirical therapy. Randomized evidence from CUPISCO supports early CGP with subsequent molecularly guided treatment after disease control with platinum‐based induction, while CUP‐specific immunotherapy studies and Japanese real‐world data demonstrate clinically meaningful activity in selected patients. Conversely, randomized tissue‐of‐origin‐directed trials have produced mixed results, underscoring the need to distinguish diagnostic prediction from proven therapeutic benefit. Major guidelines broadly agree on purposeful diagnostic evaluation, recognition of favorable subsets, and individualized management, but differ in the timing and emphasis placed on molecular testing and tissue‐of‐origin assays. These differences are particularly relevant in the Asia‐Pacific region, where access, reimbursement, turnaround time, and treatment availability vary substantially. This narrative review synthesizes contemporary evidence and proposes a practical four‐layer algorithm in which clinical urgency, tissue and biomarker readiness, and precision opportunities are assessed in parallel. The central principle is that clinically indicated therapy should not be delayed solely while awaiting molecular results; instead, empirical treatment and biomarker planning should be coordinated to preserve treatment opportunities.