In metastatic castration-refractory prostate cancer (mCRPC), state-of-the-art treatment consists of androgen biosynthesis inhibition (abiraterone), inhibition of the androgen receptor (enzalutamide), chemotherapy, or radium-223 in combination with androgen deprivation therapy (ADT). A subgroup of these patients show oligoprogression, with the progression of only a limited number of metastatic spots, while all other metastases remain controlled by ongoing systemic therapy. In a bi-institutional retrospective study, we tested the hypothesis that progression-directed therapy (PDT) targeting oligoprogressive lesions might defer the initiation of next-line systemic treatment (NEST). A total of 30 patients were diagnosed with mCRPC and experienced oligoprogression, defined as a total of three or fewer progressive lesions either at known metastatic sites and/or the appearance of new metastasis and/or local recurrence. All patients were under active ADT with or without second-line systemic treatment. All patients received PDT targeting the oligoprogressive lesions, while ongoing systemic treatment was maintained. There was median NEST-free survival of 16mo (95% confidence interval [CI] 10-22) and progression-free survival of 10mo (95% CI 6-15) with only minor radiotherapy- or surgery-related toxicity. These findings encourage further prospective trials. PATIENT SUMMARY: In patients with metastatic castration-refractory prostate cancer, surgical treatment or high-dose radiation therapy directed to only the limited number of progressive metastatic spots, while all other metastases remained controlled by ongoing systemic therapy, led to substantial postponement of next-line systemic treatment in our study.