177Lu-PSMA-617 versus Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer: a randomised, open-label, phase 2 trial (TheraP)

1703 Objectives: 177Lu-PSMA-617 is a radiolabelled small molecule that delivers β-radiation to cells expressing prostate specific membrane antigen (PSMA), with promising activity and safety in metastatic castration-resistant prostate cancer (mCRPC). We compared 177Lu-PSMA-617 and cabazitaxel in a randomised phase 2 trial. Methods: Men with mCRPC progressing after docetaxel with high PSMA tumour-expression were randomized to 177Lu-PSMA-617 (6-8.5 GBq intravenously 6 weekly up to 6 cycles) vs cabazitaxel (20 mg/m2 intravenously 3 weekly up to 10 cycles) at 11-sites in Australia. The primary endpoint was prostate specific antigen (PSA) response rate defined by ≥50% reduction (PSA50-RR). Secondary endpoints included progression-free survival (PFS) (PSA and radiographic PFS), objective response rate (ORR) (RECIST 1.1), adverse events (CTCAE v4.03), patient-reported outcomes (PROs) (EORTC QLQ-C30, PDF), and overall survival (OS). This trial is registered in ClinicalTrials.gov, NCT03392428. Results: 200 of 291 men identified as eligible on PET imaging were randomised to 177Lu-PSMA-617 (N=99) or cabazitaxel (N=101). 91% had received prior androgen receptor-directed therapy (ARDT). PSA50-RR was significantly higher in those assigned 177Lu-PSMA-617 versus cabazitaxel (66% [95%CI,56-75%] vs 37% [95%CI,27-46%]; P<0.001). PFS was significantly longer in those assigned 177Lu-PSMA-617 than cabazitaxel (rates at 1yr 19% [95%CI,12-27%] vs 3% [95%CI,1-9%], hazard ratio (HR) 0·63 [95%CI,0.46-0.86; P=0.003). ORR in 78 men with measurable disease was significantly higher with 177Lu-PSMA-617 than cabazitaxel (49% vs 24%, RR 2.12; P=0.026). Follow-up remains immature for OS. Grade 3-4 adverse events occurred in 32/98 (33%) with 177Lu-PSMA-617 vs 45/85 (55%) with cabazitaxel. Overall quality-of-life and health status were similar, with significantly better outcomes for multiple PRO domains including diarrhoea, fatigue, social functioning, insomnia, hair loss, skin rash and sore hands/feet with 177Lu-PSMA-617. Conclusions: 177Lu-PSMA-617 compared to cabazitaxel in men with mCRPC led to significantly higher PSA and ORR response rates, longer PFS, less grade 3 or 4 adverse events and significant improvements in several PRO domains. Acknowledgements: This investigator-initiated trial received support from the Prostate Cancer Foundation of Australia, Endocyte (a Novartis Company), Australian Nuclear Science and Technology Organization (ANSTO), Movember, It’s a Bloke Thing, CAN4CANCER. Results also presented at ASCO GU 2021.