Background: In PROfound, olaparib demonstrated improved radiological PFS (rPFS) and overall survival (OS) versus new hormonal agent (NHA) in patients with homologous recombination repair mutated (HRRm) mCRPC that had progressed on prior NHA. This efficacy was observed across prespecified subgroups including patients treated with prior taxane therapy and for whom intravenous cabazitaxel is an alternative treatment option. The relative efficacy of olaparib versus cabazitaxel has not been assessed in head-to-head studies. An indirect treatment comparison (ITC) was performed to simulate the comparative efficacy of olaparib and cabazitaxel in patients with HRRm mCRPC after prior taxane and NHA. Methods: Fixed-effects frequentist ITCs were conducted using efficacy data from the prior taxane subgroup of PROfound (NCT02987543) and published data from the Phase IV CARD study of cabazitaxel versus NHA after prior NHA and taxane treatment (NCT02485691). Baseline variables feasible for comparison across studies were assessed for effect modification. Efficacy analyses were performed on the hazard ratios (HR) of rPFS by independent central review and OS. The OS analysis was performed using the final PROfound OS results, which included switching from NHA to olaparib after progression, and using results that were adjusted for switching. In the absence of biomarker subgroup data, the efficacy results of the overall population in CARD were assumed generalizable to the HRRm biomarker population of PROfound, such that mutation status is not a modifier of relative treatment effect for cabazitaxel versus NHA. Results were presented for the comparison of olaparib with cabazitaxel in the BRCA1-/BRCA2-mutated (BRCAm) and BRCAm/ATM populations. Results: The ITC HR for rPFS was 0.36 (95% confidence interval 0.20–0.64) in BRCAm and 0.51 (0.31–0.84) for the BRCAm/ATM population. Without adjustment for switching in PROfound, the ITC HRs for OS in the BRCAm population and BRCAm/ATM population were 0.99 (0.55–1.78) and 0.88 (0.52–1.47), respectively; after switch adjustment, the OS HRs were 0.47 (0.12–1.79) and 0.44 (0.17–1.10), respectively. Conclusions: The ITC results suggest that olaparib is associated with significantly improved rPFS versus cabazitaxel in the treatment of BRCAm and BRCAm/ATM patients who have progressed on taxane and NHA therapy. After removing the effect of switching from NHA to olaparib in PROfound, olaparib appears associated with a non-significant OS improvement versus cabazitaxel in both populations. The results require confirmation in comparative studies. Analysis limitations include uncertainty over the efficacy of cabazitaxel versus NHA in HRRm mCRPC patients, and heterogeneity in prior taxane and NHA therapy. Clinical trial information: NCT02987543