Deutenzalutamide, an oral deuterated androgen receptor inhibitor, vs placebo for patients with mCRPC who have experienced treatment failure with abiraterone and docetaxel: Results of the HC-1119-04 phase 3 trial

5065 Background: Deutenzalutamide (HC-1119) is a novel deuterated derivative of enzalutamide with a different metabolic profile while maintaining biologic activity at a lower dose. Abiraterone and docetaxel are widely used in mCRPC, however, resistance mechanisms eventually occur. Methods: The HC-1119-04 (NCT03851640), a multicenter, randomized, double-blind phase 3 trial in China enrolled patients with mCRPC who have failed abiraterone, or failed or were not eligible for docetaxel. Patients were randomized 2:1 to deutenzalutamide (80 mg orally daily) or placebo. Stratification factors included lesion site (visceral/non-visceral), prior docetaxel treatment (yes/no). The primary endpoint was investigator-assessed radiographic PFS. Secondary endpoints included: OS, independent radiologic review committee (IRC)-assessed rPFS, ORR, and PSA response. The hazard ratio (HR) and its 95% confidence interval (CI) between the two groups were calculated using a stratified Cox proportional hazards model. Results: The HC-1119-04 study enrolled 417 subjects between April 2019 – Nov 2021, with 276 randomized to deutenzalutamide and 141 to placebo. Demographics and disease characteristics were well-balanced across treatment arms. All subjects were previously treated with abiraterone. Most of the subjects received docetaxel (68.8% vs. 68.1%); visceral lesions accounted for 27.9% in the deutenzalutamide and 27.7% in the placebo group. The study met its primary endpoint with a 42% reduction in the risk of progression or death in the deutenzalutamide arm (HR = 0.58 [95% CI: 0.439, 0.770]; P= 0.001. The median rPFS (95% CI) was 5.55 (4.830, 7.360) months for deutenzalutamide vs 3.71 (2.860, 5.490) months for placebo. Results in the pre-specified subgroups, including visceral metastases, and prior docetaxel were consistent with the overall outcome. The median OS (95% CI) was 14.98 (9.560, -) months and 11.24 (9.890, 15.510) months in the deutenzalutamide and placebo group, respectively, with an HR (95% CI) of 0.88 (0.577, 1.331). Common treatment-related adverse events (TEAE) ( > 10%) with deutenzalutamide vs placebo included: weight decreased (23.4% vs 18.6%), platelet count decreased (12.8% vs 10.7%), lymphocyte count decreased (10.2% vs 7.9%), and hypercholesterolemia (10.9% vs 4.3%), mostly grade 1/2. The overall incidence of ≥ Grade 3 study drug related TEAEs in the deutenzalutamide group was not significantly different from placebo, except anemia (6.6% vs 2.9%) and hypertension (2.2% vs 0.7%). Conclusions: Deutenzalutamide demonstrated a statistically significant improvement of PFS vs placebo in a randomized phase 3 study in patients with mCRPC who have failed abiraterone, and who failed or were intolerant to docetaxel. Deutenzalutamide was well tolerated and has the potential as additional treatment option. Clinical trial information: NCT03851640 .