Biochemical recurrence (BCR) of prostate cancer (PCa) presents a clinical challenge with limited systemic treatment options beyond androgen deprivation therapy (ADT), which carries significant morbidity. Preclinical data suggest lysosomal homeostasis, including cholesterol trafficking and pH regulation, is a therapeutic vulnerability in hormone-dependent cancers. We therefore conducted HITMAN-PC, a phase I trial evaluating Suba-Itraconazole (SI) and hydroxychloroquine (HCQ) in men with BCR Patients and Methods:The synergy of SI and HCQ was validated in hormone-sensitive and castration-resistant prostate cancer cell lines. The HITMAN-PC trial then used a rolling-six design to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of HCQ with a fixed SI dose (150 mg twice daily). Secondary endpoints included safety, PSA kinetics (PSA-PFS, time to ADT), and exploratory pharmacokinetic and lipidomic profiling.
Itraconazole showed dose-dependent cytotoxicity, with synergy in LNCaP-derived hormone-sensitive and resistant lines. Eleven patients were enrolled. Two dose-limiting toxicities at HCQ 600 mg twice daily (grade 3 diarrhea and ALT elevation) defined this level as the MTD with SI 150 mg twice daily. Common adverse events were hypertension, QTc prolongation, diarrhea, and nausea; no grade 4 events occurred. No PSA declines ≥50% were observed, though most patients achieved PSA stabilization. Median PSA-PFS, time to ADT, and metastasis-free survival were 5.5, 14.3, and 15.9 months, respectively. Lipidomic profiling revealed 240 treatment-associated lipid changes, with sphingomyelin and triacylglycerol species correlating with PSA-PFS.
Despite limited clinical activity overall, the identified lipidomic signatures provide proof-of-concept for using plasma lipidomics to monitor pharmacodynamic activity in future metabolism-targeted trials.
Cancer research communications. 2026 Mar 05 [Epub ahead of print]
Barak Talmor, Stefano Marastoni, Brandon Lau, Andrew O Yam, Nicole Yeung, Hui-Ming Lin, Zhu Juan Li, Henry Woo, Ganes Pranavan, Phillip D Stricker, Lisa G Horvath, Marianne Koritzinsky, Bradly G Wouters, Megan Crumbaker, Anthony M Joshua
The Kinghorn Cancer Centre Sydney Australia., University Health Network Toronto Canada., Garvan Institute of Medical Research Darlinghurst, NSW Australia., Princess Margaret Cancer Centre Toronto, Ontario Canada., Blacktown & Mount Druitt Hospital Blacktown, New South Wales Australia., Canberra Hospital Australia., St Vincent's Hospital Sydney Darlinghurst, NSW Australia., Chris O'Brien Lifehouse Sydney, New South Wales Australia., Princess Margaret Cancer Centre Canada., Princess Margaret Cancer Centre Toronto, ON Canada., The Kinghorn Cancer Centre Sydney, NSW Australia., The Kinghorn Cancer Centre Darlinghurst, NSW Australia.