pruxelutamide (GT0918)

P2, N=61, Completed, Suzhou Kintor Pharmaceutical Inc, | Recruiting --> Completed

Patients in part 1 regimen-finding phase received proxalutamide plus specific ETs (letrozole [cohort A], exemestane [cohort B], or fulvestrant [cohort C]) and were assessed for dose-limiting toxicity (DLT), PK, PD, and anti-tumor activity. These findings suggested favorable clinical outcomes and safety profiles of the combination of proxalutamide and fulvestrant in AR+/HR+/HER2- mBC patients who have progressed on the first-line therapy, and maybe with better efficacy in patients with lower AR/ER ratio. Trial registration: NCT20191063

Monotherapies were initiated including letrozole (2.5 mg/day on days 1-14) for cohort A, exemestane (25 mg/day on days 1-14) for cohort B, and fulvestrant (intramuscularly 500 mg once on days 1, 15 and 28) for cohort C, followed by proxalutamide 200 mg QD and ETs for in a 28-day cycle. Conclusions This study suggested a good antitumor activity and safety profile of the combination therapy of proxalutamide and fulvestrant for HR+/HER2-/AR+ mBC patients in the ≥2nd-line settings. Moreover, it may provide survival benefits for these patients, warranting further investigation in a larger population.

Proxalutamide exerted similar effects as enzalutamide, an AR antagonist prescribed for advanced prostate cancer, in decreasing AR signaling and expression of TMPRSS2 and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor...Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir...Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and decreased lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials.

Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them...Additional structural studies suggest that both the L702H and F877L mutations are important for conformational changes. This structural variability in the AR LBD could affect ligand binding as well as the resistance to antagonists.

Proxalutamide showed promising anti-tumour activity with good tolerability in patients with heavily pretreated AR mBC, supporting further investigation.

Further, Proxalutamide decreased C-reactive protein, D-Dimer and improved lymphocyte count, biomarkers for COVID-19 progression in clinical studies. Together, these results provide a strong rationale for the treatment of severe COVID-19 patients with Proxalutamide.

Proxalutamide significantly inhibited the proliferation and migration of PCa cells, and its inhibitory effect was superior to that of enzalutamide (Enz, second-generation AR antagonist). By co-targeting the AR axis and endogenous adipogenesis, a novel and promising strategy was established for proxalutamide to combat the progress of PCa. The unique effect of proxalutamide on the metabolic reprogramming of PCa provides a potential solution to overcome the resistance of current AR-targeted therapy, which will help to effectively prolong its clinical service life.

GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.

P1, N=63, Completed, Suzhou Kintor Pharmaceutical Inc, | Active, not recruiting --> Completed

GT0918 has been shown to be well tolerated and may provide potential clinical benefits to AR positive metastatic breast cancer patients . This study demonstrated triple negative in AR positive patients had more benefit.