UPLIFT Trial: Abemaciclib Safely Boosts PSMA for Better Radioligand Therapy in Advanced Prostate Cancer

The UPLIFT trial is a phase 1/2 study testing a new combo for metastatic castrate-resistant prostate cancer.Researchers at the University of California, San Francisco, designed this trial to boost the power of 177Lu-PSMA-617, a targeted radiation drug called a radioligand therapy. That drug latches onto PSMA, a protein stamped all over prostate cancer cells, and zaps tumors with radiation, but it shines brightest in patients whose scans show high PSMA levels, which not everyone has. A genetic CRISPR screen revealed CDK4/6 as a master regulator of PSMA expression in prostate cancer cells. Blocking CDK4/6 with the inhibitor abemaciclib cranks up PSMA on those cells, making tumors glow brighter on PET scans and potentially sucking in more radiation from 177Lu-PSMA-617 for better kills. The trial’s trick: a quick 14-day “lead-in” blast of abemaciclib right before each radioligand dose, priming PSMA without the grind of nonstop CDK4/6 blockade and its draining side effects like low blood counts.

For phase 1, the goal was pure safety, finding a dose that doesn’t wreck patients while paving the way for phase 2. They picked men with mCRPC that progressed after ARSI treatment, with or without taxane chemo like docetaxel, but only if scans showed PSMA-avid disease: at least three spots lighting up stronger than the liver on PSMA PET, proving the therapy had targets.

These guys were a real test case: median age 69, from 60 to 84; 78% Caucasian; starting PSA around 40.6 ng/mL on average, swinging from zero to 744 ng/mL; and 89% had already battled taxane chemo, so most were battle-hardened with shrunken options. Every one of the nine had treatment-related adverse events (TRAEs), par for advanced trials, but nothing spun out of control.

This tolerance stands out in mCRPC, where piling on therapies often sparks chaos like infections from low white cells or kidney woes from radiation. The short abemaciclib pulse dodges heavy neutropenia or gut meltdowns from prolonged use, yet still flips the PSMA switch. No surprise spikes in xerostomia (that endless dry mouth) or marrow crash beyond what 177Lu-PSMA-617 does solo, per trials like VISION with its 13% grade 3+ rates. Phase 2 rolls on now, measuring PSA50 or 90 drops, scan progression-free survival and overall survival versus radioligand alone. If it delivers, this could supercharge PSMA therapy access, especially for dim-PSMA cases, fitting the wave of radiopharma tweaks in prostate cancer alongside ADCs or CRISPR finds.

Clinical trial.