Epigenetic Therapy with Panobinostat Combined with Bicalutamide Rechallenge in Castration-Resistant Prostate Cancer

Area of Science:

• Oncology
• Pharmacology
• Cancer Biology

Background:

• Castration-resistant prostate cancer (CRPC) often develops resistance to antiandrogen therapies like bicalutamide.
• Histone deacetylase inhibitors (HDACIs) like panobinostat are being investigated for their potential to overcome treatment resistance.
• Androgen receptor (AR) signaling plays a critical role in prostate cancer progression and resistance mechanisms.

Purpose of the Study:

• To evaluate the efficacy of panobinostat in restoring bicalutamide sensitivity in a CRPC model.
• To assess the safety and efficacy of the combination of panobinostat and bicalutamide in CRPC patients resistant to second-line antiandrogen therapy (2ndLAARx).

Main Methods:

• In vitro and xenograft models were used to test drug interactions on tumor cell growth and AR signaling.
• A Phase I/II clinical trial was conducted, randomizing 55 CRPC patients to receive panobinostat (40 mg or 20 mg) with bicalutamide.
• The primary endpoint was radiographic progression-free (rPF) survival at 36 weeks.

Main Results:

• The panobinostat/bicalutamide combination demonstrated synergistic antitumor effects and reduced AR activity in preclinical models.
• The 40 mg panobinostat arm showed a higher probability of remaining rPF (47.5%) compared to the 35% threshold.
• Adverse events were observed, with thrombocytopenia and fatigue being common grade ≥3 events in the higher dose arm, but toxicity was generally manageable with dose adjustments.

Conclusions:

• The combination of 40 mg panobinostat with bicalutamide improved rPF survival in CRPC patients resistant to 2ndLAARx.
• Panobinostat toxicity was tolerable, supporting its use in combination therapy with appropriate dose modifications.
• Epigenetic therapy with HDACI can overcome AR-mediated resistance to bicalutamide, offering clinical benefit in CRPC patients.