A combination therapy pairing 177Lu (Pluvicto), a targeted radioligand, with gotistobart (BNT316/ONC-392), an innovative anti-CTLA-4 antibody, is offering new hope for men with metastatic castration-resistant prostate cancer. The PRESERVE-006 trial (NCT05682443), an open-label, randomized, multicenter phase 1/2 study, is exploring this novel approach in patients who have progressed after androgen receptor pathway inhibitors (ARPIs).

Early results from the phase 1 dose-escalation phase, reported as of December 20, 2024, demonstrate a manageable safety profile and encouraging antitumor activity, suggesting that this combination could enhance the effectiveness of existing treatments for this challenging disease.

In the trial’s phase 1 portion, 24 patients with a median age of 70.5 years (ranging from 52 to 86) were randomized to receive 177Lu at 7.4 GBq (200 mCi) every 6 weeks for up to six doses, either alone (control arm) or combined with gotistobart at three dosing regimens: 3 mg/kg every 4 weeks , 6 mg/kg every 6 weeks , or 10 mg/kg every 6 weeks, for up to 13 doses. The primary goal was to assess safety and select two gotistobart doses for the phase 2 dose optimization study, with a key secondary endpoint being the PSA50 response—a ≥50% decline in prostate-specific antigen (PSA) levels, a critical marker of tumor response.

The safety data are promising. No deaths, dose-limiting toxicities, or severe (grade 4–5) treatment-related adverse events (TRAEs) were reported across any group.

On the efficacy front, the combination therapy outperformed 177Lu alone.
In the efficacy-evaluable population, 4 of 6 patients (66.7%) in the 3 mg/kg  and 3 of 6 patients (50%) in the 10 mg/kg arm achieved a PSA50 response, compared to only 1 of 6 patients (16.7%) in the 177Lu-alone control arm. These results, though based on a small sample, indicate that adding gotistobart may significantly enhance 177Lu’s ability to reduce tumor burden, likely by counteracting Treg-mediated immune suppression in the TME. The median follow-up varied by arm—10.9 months for 3 mg/kg, 5.4 months for 10 mg/kg, 2.6 months for 6 mg/kg, and 6.5 months for the control arm—suggesting that longer-term data could further clarify the combination’s benefits.

The PRESERVE-006 trial’s early findings highlight the potential of combining 177Lu’s targeted radiation with gotistobart’s immune-modulating effects. The higher PSA50 rates in the combination arms compared to the control arm suggest that depleting Tregs in the TME may amplify 177Lu’s antitumor activity, offering a synergistic approach to tackling mCRPC.

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