Table 1.

Key safety and efficacy findings for ²²³Ra plus enzalutamide in clinical trials and real-world studies.

Reference	Study design	Treatment groups (n)	Key findings
Phase 3
Gillessen et al. (70)	Randomized, open-label, multicenter	223Ra + Enz + BHA (82)	Safety	Without concomitant BHAs: two-fold increased risk of fractures with 223Ra + Enz vs. Enz With concomitant BHAs: fracture risk mostly eliminated with either regimen
		Enz + BHA (87)
		223Ra + Enz (36)	Efficacy	Not yet available
		Enz (32)
Phase 2
Maughan et al. (63)	Prospective, randomized, open label, single center	223Ra + Enz (35) Enz (12)	Safety	Fracture incidence: 5.7% with 223Ra + Enz vs. 0% with Enz Several any-grade AEs were more common with 223Ra + Enz than with Enz (incidence difference of ≥15%), including anemia (26% vs. 7%), constipation (29% vs. 0%), diarrhea (54% vs. 7%), fatigue (46% vs. 21%), flu-like symptoms (17% vs. 0%), lymphocyte count decrease (51% vs. 29%), nausea (46% vs. 7%), neutrophil count decrease (40% vs. 0%), platelet count decrease (20% vs. 0%), and white blood cell count decrease (57% vs. 0%)
			Efficacy	Median OS: 30.8 mo (CI 17.9–NE) with 223Ra + Enz vs. 20.6 mo (16.8–NE) with Enz (p = 0.73) Median rPFS: 11.5 mo (CI 9.2–29) with 223Ra + Enz vs. 7.35 mo (2.8–NE) with Enz (p = 0.96) Median PSA-PFS2: 18.7 mo (CI 12.2–42.8) with 223Ra + Enz vs. 8.4 mo (CI 5.52–NE) with Enz (P = 0.033)
Shore et al. (64)	Open-label, single-arm, multicenter	223Ra + Enz (39)	Safety	54% of patients had TRAEs, most commonly fatigue (25.6%), nausea (17.9%) and anemia (12.8%) No serious TRAEs occurred Fractures occurred in 5.1% of patients
			Efficacy	61.5% of patients had no radiographic progression
McDermott et al. (65)	Open-label, single-arm, multicenter	223Ra + Enz (45)	Safety	Fractures occurred in 8.9% of patients during treatment; a further 28.9% of patients developed fractures after completing treatment, giving a cumulative incidence of 37.8% by study end No treatment-related deaths occurred Grade 3–4 TRAEs occurred in 24.4% of patients, most commonly fatigue and neutropenia (both 6.7%)
			Efficacy	Median time to PSA progression: 18.1 mo (95% CI 12.68–22.60) Median time to radiological or clinical progression: 28.0 mo (95% CI 22.54–NR) Mean time for OS: 34.8 mo (median NR)
Real-world
Tombal et al. (66)	Prospective, multicenter, observational	Concurrent 223Ra + Enz + BHA (25) Layered 223Ra + Enz + BHA (95) Any 223Ra regimen + BHA (566) Concurrent 223Ra + Enz (21) Layered 223Ra + Enz (110) Any 223Ra regimen (899)	Safety	Fracture incidence with concurrent 223Ra + Enz, layered 223Ra + Enz, or any 223Ra regimen was 8% (2/25), 2% (2/95), and 3% (19/566), respectively, in patients who received concomitant BHAs and 5% (1/21), 4% (4/110), and 6% (51/899), respectively, in patients who did not receive concomitant BHAs Any-grade TRAEs occurred in 37, 28 and 35% of patients in the concurrent, layered or any 223Ra regimen groups, respectively; corresponding values for grade ≥ 3 TRAEs were 13, 8 and 11%
			Efficacy	Median OS: 22.2 mo (95% CI 13.7–26.8) in the concurrent group, 16.5 mo (95% CI 13.9–19.5) in the layered group and 15.6 mo (95% CI 14.6–16.5) in the any 223Ra regimen group
Trieu et al. (67)	Retrospective (single-center EHR data)	Concurrent 223Ra + Enz + BHA (33) a	Safety	Fractures occurred in 6.1% of patients
Shore et al. (68)	Retrospective (multicenter EHR data)	Concurrent 223Ra + Enz (44) Layered 223Ra + Enz (123) Any 223Ra regimen (625)	Safety	Pathological fracture incidence with concurrent 223Ra + Enz, layered 223Ra + Enz, or any 223Ra regimen was 9, 12, and 10%, respectively
			Efficacy	Median OS: 19.1 mo (95% CI 12.3–NR) in the concurrent group, 15.2 mo (95% CI 11.6–16.3) in the layered group and 15.2 mo (95% CI 13.2–16.3) in the any 223Ra regimen group

^aOther treatment groups were included in this study. ²²³Ra, radium-223; AE, adverse event; BHA, bone health agent; CI, confidence interval; EHR, electronic health records; mo, months; Enz, enzalutamide; NE, not evaluable; NR, not reached; OS, overall survival; rPFS, radiographic progression-free survival; PSA-PFS2, time from start of protocol therapy to PSA progression on subsequent therapy; PSA, prostate-specific antigen; TRAE, treatment-related adverse event.