In a first-in-human Phase 1/2 study of HLD-0915 in metastatic castration-resistant prostate cancer, 31% of all 31 treated patients achieved a PSA50 decline, and 23% achieved PSA90; among the 22 patients completing at least two cycles, PSA50 and PSA90 rates rose to 59% and 32%, respectively. All five patients with RECIST-measurable disease at baseline who underwent on-treatment imaging had partial responses at first assessment, and 13 of 16 evaluated patients showed ctDNA tumor fraction reductions of 70% to 99.9%. Safety was favorable across doses, with low rates of treatment-related adverse events and few grade ≥3 events; no thrombocytopenia was observed.
Halda Therapeutics reported the data from its ongoing dose-escalation and expansion study (NCT06800313) of HLD-0915, an oral, once-daily RIPTAC modality designed to exploit AR expression to disable BRD4 selectively in tumor cells. The trial enrolled heavily pretreated mCRPC patients who had progressed on at least one AR pathway inhibitor and could have received up to two prior taxanes and one radioligand therapy. Dosing spanned 12.5 to 100 mg in 21-day cycles. Based on emerging activity and tolerability, 25 mg and 50 mg were identified as recommended doses for Phase 2 expansion, which is slated to begin in late 2025. The program holds FDA Fast Track status.
Strategically, the readout positions HLD-0915 as a potential route around AR-centric resistance without imposing a biomarker gate that narrows enrollment. The signal across heterogeneous AR alterations, paired with an oral regimen and early-onset PSA declines (median time to PSA50 of 37 days), points to an operationally straightforward profile relative to radioligand sequencing or combination-intense strategies. Importantly, the absence of the thrombocytopenia typical of BET inhibition suggests a differentiated pharmacology that could support longer-term dosing and combination optionality, although the dataset is still small and higher-dose lab abnormalities warrant continued vigilance.
For sites and CROs, the operational footprint is attractive: a daily oral agent, 21-day cycles, and manageable monitoring without infusion infrastructure or radiation safety requirements. If ctDNA continues to track with clinical response, central-lab liquid biopsy logistics may become a core element of study conduct and potentially enable adaptive decisions, but assay harmonization and sampling cadence will matter. Given the predominance of bone-predominant disease in prostate cancer, reliance on PSA and ctDNA alongside radiographic criteria aligned with PCWG3 will be critical to avoid interpretability gaps. Community oncology and urology networks could participate broadly if eligibility remains biomarker-light and safety stays favorable at the RP2D.
For sponsors and regulators, the pressure points are clear. The field’s post-ARPI, post-taxane landscape is fragmented with PSMA radioligands, PARP inhibitors in HRR-mutated disease, and emerging bispecifics and ADCs. Designing a Phase 2/3 path that secures a clean comparator and clinically persuasive endpoints—durability of PSA response, radiographic PFS, time to symptomatic skeletal events, and time to next therapy—will determine whether this signal translates into a registrational trajectory. Fast Track can compress timelines, but only if durability and rPFS replicate across broader, less selected cohorts.
What to watch next is durability at the 25 mg and 50 mg doses, exposure–response relationships, and consistency of benefit in patients with extensive prior radioligand exposure or dual-taxane histories. Combination plans with ARPIs, PARP inhibitors, or sequential use after PSMA therapy will be a litmus test for commercial relevance and trial complexity. If the safety profile holds with longer exposure and the ctDNA signal correlates with radiographic outcomes, Halda could justify an adaptive Phase 2/3 design. The unresolved risks are typical of early oncology signals: small RECIST sample size, enrichment among patients persisting beyond two cycles, and the need to demonstrate durable control rather than transient biomarker shifts.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
