Treatment options in platinum-refractory male germ cell cancers: current standards and future directions

Germ cell cancers (GCCs) represent the most common malignant tumours among men up to the age of 40 years. GCCs are characterised by high cure rates of >99% for localised stage I disease, but even at advanced metastatic stages, 67%-96% of patients can be cured with multimodal treatment approaches. The high curability owes to an exceptional responsiveness to cisplatin-based chemotherapy. However, about 30% of patients with metastatic disease eventually relapse after first-line multimodality treatment. At first relapse, salvage treatment still cures approximately 50% of patients. Platinum-based chemotherapy remains the standard of care in this setting, administered either as conventional-dose cisplatin-based regimens or as high-dose carboplatin-based combination chemotherapy. Across multiple large retrospective cohorts, high-dose chemotherapy has repeatedly been associated with superior progression-free and overall survival compared with conventional-dose approaches, although definitive prospective evidence is awaited. Patients suffering second or multiple relapses are considered platinum-resistant and face a very dismal prognosis with a life expectancy generally limited to less than 12 months. The mainstay of treatment in this setting is still conventional cytotoxic chemotherapy since no molecularly targeted treatments have shown clinically meaningful activity, to date. However, Claudin-6 (CLDN6)-directed approaches appear the most promising avenue of new treatment options in this situation. In this narrative review, we outline established and emerging treatment opportunities for this rare but challenging clinical scenario of platinum-resistant GCCs. This review provides a focused and up-to-date synthesis of therapeutic options for multiply relapsed, platinum-refractory GCCs, with a particular emphasis on late-line treatment sequencing and emerging biomarker-driven strategies, including CLDN6-directed therapies.