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.

GT0918, a full AR antagonist without agonist effect, has high binding affinity to AR with AR protein down-regulation activity. GT0918 is demonstrated to be well tolerated with a favourable PK profile and exhibits promising antitumour activity in CRPC. CLINICALTRIALS: gov identifier CTR20150501.

LC-Q/TOF-MS was then used for analyzing intracellular metabolites in the four PCa cells before or after administration of proxalutamide and two other AR antagonists (bicalutamide and enzalutamide). Proxalutamide influenced the glutamate metabolism, redox homeostasis and pyrimidine synthesis in PCa cells, and these changes on metabolic and redox status in PCa cells may be associated with the blockade of AR signaling pathways.

LC-Q/TOF-MS was then used for analyzing intracellular metabolites in the four PCa cells before or after administration of proxalutamide and two other AR antagonists (bicalutamide and enzalutamide). Proxalutamide influenced the glutamate metabolism, redox homeostasis and pyrimidine synthesis in PCa cells (Fig.1c and 1d), and these changes may be associated with the blockade of AR signaling pathways. Source of Funding: Supported by National Nature Science Foundation of China (81703608) and Nanjing Medical Science and Technique Development Foundation(QRX17049)

LC-Q/TOF-MS was used to analyze intracellular metabolites before or after the administration of proxalutamide and two other clinical AR antagonists (bicalutamide and enzalutamide). However, the effects of the two other antagonists on these discriminant metabolites were ambiguous, and no changes in these metabolites were found in AR-negative cells. Our findings indicate that proxalutamide has inhibitory effects on glutamine metabolism, redox homeostasis and de novo pyrimidine synthesis in AR-positive PCa cells that enhance the cellular sensitivity to proxalutamide.

Proxalutamide (GT0918) administrated orally once a day is well tolerated in late-stage pts. No DLT has occurred at maximum dose 500 mg. Pts with AR positive biomarker could have better clinical outcomes with GT0918 treatment.