Background: [¹⁷⁷Lu]Lu-PSMA-617 improves outcome in men with metastatic, PSMA positive CRPC post androgen pathway inhibitor therapy and taxane chemotherapy compared to standard care (excluding chemotherapy, immunotherapy, radium-223 and investigational drugs; Sartor et al, NEJM 2021). The relative efficacy, adverse event experience and impact on QOL of [¹⁷⁷Lu]Lu-PSMA-617 compared to docetaxel chemotherapy in this patient population is unknown. We hypothesize that [¹⁷⁷Lu]Lu-PSMA-617 will improve radiographic PFS (rPFS) compared to docetaxel chemotherapy with a favourable safety and tolerability profile. Methods: CCTG PR21 is a Canadian Cancer Trials Group randomized phase II trial with a primary objective to compare rPFS between [¹⁷⁷Lu]Lu-PSMA-617 7.4 GBq (+/- 10%) IV q 6 weekly (maximum 6 cycles) versus docetaxel 75 mg/m² q 3 weekly (maximum 12 cycles). Secondary objectives are to compare the two arms with respect to: 6-month PFS rate (PCWG3 and RECIST 1.1), second rPFS after crossover to the alternate therapy, time to commencement of 3^rd line systemic therapy, OS, PSA decline from baseline, clinical benefit rate and adverse events. Tertiary objectives include evaluation of QOL (FACT-P and EQ5D-5L), cost effectiveness, ctDNA and radiographic based prognostic and predictive biomarkers, dosimetry based approach to measurement of [¹⁷⁷Lu]Lu-PSMA-617 activity and creation of tissue and image biobanks. Key eligibility criteria include: mCRPC with PSMA positive disease using ¹⁸F or ⁶⁸Ga radionuclide label, progression on ADT + ARPI therapy (using PSA, RECIST 1.1 or PCWG3 criteria) and adequate organ function. Statistical Design: Patients are allocated in 1:1 ratio to [¹⁷⁷Lu]Lu-PSMA-617 or docetaxel balanced for stratification factors of ECOG PS, LDH, visceral metastases, previous docetaxel in the castration sensitive setting > 1 year prior to enrollment as well as centre. Assuming a 6-month median rPFS for the control group, the detection of a hazard ratio (HR) of 0.67 with 80% power using a 1-sided 5% level test will require accrual of 200 participants in 24 months with 12-month follow-up to trigger the primary analysis. Conduct to Date: Study activation Dec 17 2020. Enrollment as of January 31 2022: 25. The DSMC last reviewed and recommended continuation of the trial in December 2021. Clinical trial information: NCT04663997.