Background: [¹⁷⁷Lu]Lu-PSMA (LuPSMA) is currently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Little is known about the efficacy of treatment in pts with subsequent progression after LuPSMA. In this single-centre retrospective analysis, we evaluated efficacy of first subsequent therapy following LuPSMA. Methods: 234 mCRPC pts who received LuPSMA at the Peter MacCallum Cancer Centre from 2015-2022 were analysed. Pts were excluded if they did not receive any subsequent treatment (n=136), if they received the initial course of LuPSMA in combination with another therapy (n=10), or if insufficient follow-up data were available (n=15).Retreatment withLuPSMA was considered a subsequent line of therapy. Data collected included 50% PSA response rate (PSA-RR), PSA-progression free survival (PSA-PFS) and overall survival (OS). Survival outcomes were calculated using Kaplan-Meier analysis. Results: Of 73 evaluable pts, 32 were retreated with LuPSMA (median 2 cycles); and 41 commenced a new line of systemic therapy. In the LuPSMA retreatment group, the PSA-RR was 44%, median PSA-PFS was 3.8 months and median OS 14.8 months. In pts who changed to a new line of treatment, cabazitaxel was the most commonly prescribed therapy (n=25), followed by docetaxel (n=7), and single-agent carboplatin (n=4), in addition to carboplatin/etoposide, mitoxantrone, olaparib, capecitabine and a clinical trial (n=1 for each). PSA-RR was 12%, median PSA-PFS was 3.5 months and median OS 6.6 months. Conclusions: This retrospective data demonstrates that retreatment with LuPSMA is associated with benefit, though this is reduced compared to initial treatment. In our cohort of pts who commenced a new line of therapy, most were not suitable for retreatment with LuPSMA, potentially reflecting de-differentiated and more aggressive disease phenotypes. In those not suitable for LuPSMA retreatment, other systemic therapy appears to have limited benefit, highlighting the lack of effective salvage options and raising questions about treatment sequencing.