Background
Darolutamide (Daro) and enzalutamide (Enza) are next generation androgen receptor inhibitors. Daro does not significantly penetrate the blood-brain barrier, which may reduce cognitive impairment. ODENZA is a prospective, cross-over, preference, randomized phase II trial of Daro and Enza in patients (pts) with mCRPC. Pts (n=249) were randomized 1/1 to receive Daro 1200 mg/d for 12 weeks followed by Enza 160 mg/d for 12 weeks or the reverse sequence. Numerically more pts with early mCRPC preferred Daro over Enza, although the difference did not reach significance (Colomba et al, ASCO 2021).
Methods
Cognitive assessment using computerized cognitive tests (COGSTATE) was a key secondary endpoint of ODENZA. Changes from baseline were described by assessing each 12 weeks period. Individual tests (Detection Test: psychomotor function, Identification Test: visual attention, One Back Test: working memory, International Shopping List Test (ISL): verbal learning, International Shopping list Test Delayed Recall (ISRL): verbal memory, Groton Maze Learning: executive function) were used and three composite scores (eg ISL/ISRL for episodic memory) were created. Treatment effects were analyzed using Mixed-Effects Model Repeated Measures. Effect sizes were classified as clinically meaningful when greater than or equal to 0.5.
Results
Cognitive data were available in 193 pts. Performance on verbal learning (ISL) was significantly better with Daro at each of the post-baseline assessments, within both periods and when averaged over periods. Effects were clinically meaningful at the second period (-0.62, p=0.0001) and overall (-0.54, p<0.0001). Performance on verbal memory (ISRL) was significantly better with Daro at the second period and when averaged over periods, although the effect sizes were less meaningful (second period: -0.4, p=0.01 and overall: -0.29, p=0.0075). No difference in other tests was found. The composite scores reported a moderate benefit in episodic memory after treatment with Daro compared to Enza.
Conclusions
In early mCRPC, Daro was associated with a statistically significant benefit in verbal learning and verbal memory compared to Enza.