<p>Treatment options for metastatic prostate cancer have evolved and diversified considerably in recent years. In the hormone-sensitive setting (mHSPC), the combination of androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPI) or abiraterone + prednis(ol)one (Abi), optionally combined with docetaxel, represents the current standard of care. Prior therapy, the principle of switching the mechanism of action, and the patient’s individual molecular genetic profile substantially influence treatment selection in the metastatic castration-resistant setting (mCRPC). Testing for genes involved in homologous recombination repair (<i>HRR</i>), particularly <i>BRCA1/2</i>, is essential for the indication of poly(ADP-ribose) polymerase inhibitors (PARPI), which can be used as monotherapy or in combination with an ARPI/Abi, and has prognostic as well as familial implications. Radioligand therapy with lutetium (¹⁷⁷Lu) vipivotide tetraxetan has also gained increasing importance. It is indicated for mCRPC after prior treatment with ARPI/Abi and taxane chemotherapy, and may already play a&#xa0;role in the first-line mCRPC setting following treatment with darolutamide + ADT + docetaxel in mHSPC. This article presents current guideline recommendations for mHSPC and mCRPC, summarizes the underlying evidence, and provides practical guidance for treatment selection based on prior therapy and individual genetic profiles in order to support optimal decision-making in an increasingly complex therapeutic landscape.</p>