Can TGF-β inhibition (galunisertib) enhance response to enzalutamide in metastatic castration-resistant prostate cancer (mCRPC)?: Results from a randomized phase II trial.

5056 Background: Resistance to androgen receptor (AR)-directed therapies is a major challenge in advanced prostate cancer, and enzalutamide shows limited activity after progression on abiraterone. Aberrant transforming growth factor-β (TGF-β) signaling promotes prostate cancer progression and contributes to resistance to AR-directed therapies. Preclinical studies suggest TGF-β inhibition may overcome resistance to enzalutamide. We hypothesized that combining TGF-β receptor I kinase inhibitor, galunisertib, with enzalutamide may delay enzalutamide resistance in patients with mCRPC who have progressed on abiraterone. Methods: This multicenter, randomized phase II trial enrolled chemotherapy-naïve mCRPC patients with disease progression on abiraterone. There was a cycle 1 safety run-in for the first 6 patients, followed by a randomized phase with patients assigned 3:2 to receive galunisertib plus enzalutamide or enzalutamide alone. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included PSA response, overall survival (OS), safety, and tolerability. rPFS and OS were compared between arms using Cox regression, with medians estimated by Kaplan-Meier method. Results: Of 61 patients randomized, 60 received treatment: 23 with enzalutamide and 37 with galunisertib plus enzalutamide. There was no significant difference in rPFS between the combination and enzalutamide arms (HR 1.23; 95% CI: 0.72, 2.11; p =0.44), with a median rPFS of 5.6 and 7.3 months, respectively. The OS was also similar between the two groups (HR 1.00; 95% CI: 0.55, 1.83, p =1.00), with a median OS of 21.6 months in the combination arm and 24 months in the enzalutamide arm. PSA30 response was seen in 22% of patients in the combination arm vs. 35% in the enzalutamide arm ( p =0.30), and PSA50 response in 19% vs. 26%, respectively ( p =0.50). The most common treatment-related adverse events (AEs) were fatigue, anorexia, and nausea. Grade 3-4 treatment-related AEs occurred in 11% of patients in the combination arm vs. 13% in the enzalutamide arm. Conclusions: The addition of galunisertib to enzalutamide did not improve the rPFS, OS, or PSA response compared to enzalutamide alone in patients with chemotherapy-naïve mCRPC with disease progression on abiraterone. These findings do not support further development of galunisertib plus enzalutamide in patients with mCRPC. Clinical trial information: NCT02452008 . Baseline characteristics of randomized patients. N(n=61) Enzalutamide(n=24) Galunisertib + Enzalutamide (n=37) P Age, median (range) 51 72 (57, 84) 68 (53, 85) 0.06 Race, n (%) 58 1.00 White 17 (81.0) 30 (81.1) Other 4 (19.0) 7 (18.9) Ethnicity, n (%) 60 0.66 Hispanic 0 (0.0) 2 (5.4) Non-Hispanic 21 (91.3) 33 (89.2) Unknown 2 (8.7) 2 (5.4) ECOG, n (%) 55 0.16 0 12 (54.5) 24 (72.7) 1 10 (45.5) 9 (27.3)