A phase 1b/2 study evaluating the activity of tinengotinib in combination with androgen receptor pathway inhibitors (ARPIs) in patients with metastatic castration resistant prostate cancer (mCRPC).

TPS290 Background: Androgen receptor pathway inhibitors (ARPIs) are standard life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC), but patients ultimately progress on these agents. Resistance has been shown to occur in part via lineage plasticity mediated by increased activity of kinases including JAK1 and FGFR. Preclinical studies have shown that ARPI sensitivity can be restored by inhibiting these kinases. Tinengotinib is an orally bioavailable, potent multi-kinase inhibitor that targets JAK1 and receptor tyrosine kinases (FGFRs, VEGFRs). We hypothesize that in patients with mCRPC who are progressing on ARPIs, the addition of tinengotinib will restore sensitivity to ARPIs and result in objective responses. Methods: This is a multi-center, phase 1b/2 study of tinengotinib plus either abiraterone/prednisone or enzalutamide in patients with mCRPC. Eligible patients must be on ongoing therapy with abiraterone/prednisone or enzalutamide started at least 90 days prior to study participation consent and progressing by Prostate Cancer Working Group 3 (PCWG3) criteria. Tinengotinib will be added to abiraterone/prednisone or enzalutamide at the time of progression. Phase 1b (N = up to 24) uses a 3+3 de-escalation schema to assess the safety and tolerability of tinengotinib with either abiraterone/prednisone or enzalutamide. The starting dose of tinengotinib will be 10 mg PO QD, with the possibility of de-escalation to 8 mg PO QD if a combination is not tolerated. Phase 2 employs a two-stage Simon minimax design; patients will be enrolled to evaluate the safety and efficacy of the recommended phase 2 dose (RP2D) of tinengotinib with abiraterone acetate/prednisone or enzalutamide (N = 32). Since abiraterone acetate and enzalutamide target the same pathway, response will be evaluated in combination in the signal-seeking phase 2 portion of the study. As of October 2024, 2 patients have been enrolled in phase 1b across 1 site. Enrollment for phase 2 is expected to begin in January 2025. Clinical trial information: NCT06457919 .