Introduction <p>This study aimed to evaluate the prognostic value of baseline, interim, and change-based (Δ) volumetric parameters derived from PSMA PET/CT imaging in predicting PSA progression-free survival (PSA-PFS) and overall survival (OS) in bone-dominant metastatic castration-resistant prostate cancer (mCRPC) patients treated with [¹⁷⁷Lu]Lu-PSMA-617.</p> Methods <p>This retrospective study included 56 bone-dominant mCRPC patients who underwent [⁶⁸Ga]Ga-PSMA PET/CT imaging before and after two cycles of [¹⁷⁷Lu]Lu-PSMA therapy. Quantitative parameters, including SUVmean, PSMA tumor volume (PSMA-TV), and total lesion PSMA activity (TL-PSMA), were extracted using a fixed threshold of SUV ≥ 3. Δ values were calculated as the relative change between baseline and interim scans. Associations with PSA-PFS and OS were analyzed using Cox regression and Kaplan–Meier survival analyses.</p> Results <p>The presence of new lesions on interim PSMA PET/CT and a reduction of PSMA-TV_(Bone) ≤ 10.7% were identified as independent predictors of shorter PSA-PFS (<i>p</i> = 0.022 and <i>p</i> = 0.043, respectively). For OS, an interim PSMA-TV_(Bone) &gt; 310.3 mL remained an independent prognostic factor both in the entire cohort (<i>p</i> &lt; 0.001) and in the subgroup without early PSA progression (<i>p</i> = 0.002). While baseline SUVmean values were associated with PSA-PFS, no significant association with OS was observed.</p> Conclusion <p>In bone-dominant mCRPC patients treated with [¹⁷⁷Lu]Lu-PSMA, ΔPSMA-TV_(Bone) ≤ 10.7% and the presence of new lesions were independent predictors of PSA-PFS, while interim bone tumor volume was significantly associated with OS. These findings highlight the clinical relevance of bone-specific volumetric parameters, which may serve as a potential alternative to whole-body tumor assessments by providing more practical and targeted prognostic insights in this patient population.</p>