Nonagenarians with metastatic castration-resistant prostate cancer (mCRPC) are often underrepresented in prostate cancer research due to their limited numbers among treated populations. For this group, traditional chemotherapy carries significant side effects that can severely impact quality of life. Targeted therapy designed to selectively bind to prostate cancer cells expressing the prostate-specific membrane antigen (PSMA) presents a promising alternative, particularly for those with widespread metastatic disease and contraindications to chemotherapy. This retrospective case series evaluated the response, side effects, and quality of life of three nonagenarian patients with mCRPC who received Pluvicto (177Lu-PSMA-617/177Lu-vipivotide tetraxetan) as standard care at BAMF Health in Grand Rapids, Michigan, USA. Prior to treatment, all patients underwent baseline PSMA PET/CT to confirm PSMA-expressing disease and assess eligibility. They then received standard cycles of 200 mCi Pluvicto every six to eight weeks, followed by a 24-hour single photon emission computed tomography (SPECT)/computed tomography (CT) scan to assess uptake and response. Blood work, including prostate-specific antigen (PSA) levels and a comprehensive review of hematology and chemistry parameters, was conducted before treatment and every two to three weeks. Total-body PSMA-positron emission tomography/CT with Illucix (Ga-68 PSMA-11/Ga-68 gozetotide) was performed for initial assessment and at restaging as needed. All patients showed substantial reductions in tumor burden, as measured by PSA levels and SPECT/CT. Two patients experienced a >
70% reduction in PSMA-expressing tumor volume, with PSA nadirs ranging from an 84% to 98% reduction from baseline. Adverse events were mild, including low-grade xerostomia in two patients and a progression from grade 1 to grade 2 anemia in two patients. Only one patient did not complete all six cycles due to disease progression after the fourth cycle. Pluvicto appears to be a promising treatment option for medically fragile nonagenarians with mCRPC. In this case series, the therapy demonstrated strong clinical and radiographic responses, including significant PSA reductions, underscoring its potential efficacy in this population. Its favorable safety profile and minimal toxicities further support its use in these medically vulnerable patients. However, larger studies are needed to enable a more comprehensive analysis and establish the statistical significance of these findings.