Enzalutamide + ribociclib (CDK4/6) misses PSA50 bar but extends rPFS/OS in RB+ mCRPC

Enzalutamide is an androgen receptor (AR) inhibitor and ribociclib is an oral CDK4/6 inhibitor intended to “re-awaken” RB tumor suppressor function by preventing RB hyperphosphorylation; RiboX (Phase Ib/II; NCT02555189) enrolled taxane‑naïve mCRPC with retained RB expression and established RP2D as ribociclib 600mg QD (D1–21) + enzalutamide 160mg QD (D1–28). In Phase II, PSA50 at 12 weeks was 75% with enzalutamide alone (n=12) vs 82% with the combination at RP2D (n=34), which did not beat the pre-specified PSA50 null (≤78%) despite numerically higher activity; by comparison, in chemo‑naïve mCRPC enzalutamide’s benchmark rPFS in PREVAIL was ~20.0 months (vs placebo). Combination outcomes were numerically longer for median rPFS (27.0 vs 10.9 months; evaluable n=30 vs 12), PSA PFS (14.8 vs 10.1 months; n=34 vs 12), and OS (58.1 vs 31.2 months; n=34 vs 12), but interpretation is constrained by small, modified design and wide CIs; key combination TEAEs included fatigue (59%), nausea (26.9%), neutropenia (26.7%; grade 3 12%), diarrhea (20.9%), plus infrequent arrhythmia (2.9%) and seizure (2.9%).