RECIP 1.0 + PSA for response assessment in mCRPC patients treated with 225Ac / 177Lu PSMA combination therapy

Abstract Background: Targeted alpha therapy (TAT) with 225Ac has shown promising results in metastatic castration-resistant prostate cancer (mCRPC) patients pre-treated with [177Lu]Lu-PSMA radioligand therapy (RLT). A combination treatment regimen adding 177Lu to decreased 225Ac activities may improve toxicity profile while maintaining sufficient anti-tumor effect. We therefore evaluated clinical and image-based response parameters in patients treated with 225Ac-/177Lu-PSMA combination therapies (ALCT). Results: Complete response (RECIP-CR), partial response (RECIP-PR), stable disease (RECIP-SD), progressive disease (RECIP-PD) according to RECIP 1.0 was observed in 0/25 (0%), 12/25 (48%), 9/25 (36%) and 4/25 (16%) patients, respectively. Response by RECIP+PSA was observed in 14/25 (56%) patients and progression by RECIP+PSA in 8/25 (32%) patients. Interrater reliability for visual RECIP was substantial (κ=0.757, p<0.001), while agreement between visual and quantitative RECIP was almost fully congruent (κ=0.879, p<0.001). OS did not significantly vary among the four different therapy regimens (p>0.05). When grouping patients with declining / stable PSA as responders, these patients showed no significant difference in overall survival compared to patients with progressive PSA after ALCT (p =0.312). Similarly, there was no significant difference in median overall survival between patients without RECIP-progression (RECIP-PR + RECIP-SD) and patients with RECIP-progression (RECIP-PD) (p>0.05), but when applying the composite classification, RECIP+PSA responders survived significantly longer compared to patients with RECIP+PSA progression (p=0.049). Conclusions: ALCT is a promising therapeutic regimen that may prolong survival in patients who progress during [177Lu]Lu-PSMA RLT. Our results motivate to further investigate the use of RECIP+PSA as tool for response assessment and for overall survival prediction in mCRPC under ALCT.