The UpFrontPSMA trial, a randomized Phase II study, has revealed that the addition of lutetium-PSMA-617 to docetaxel significantly improves outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC). The study, led by Arun Azad and conducted across 11 Australian centers, compared sequential lutetium-PSMA-617 and docetaxel versus docetaxel alone in de novo high-volume mHSPC, demonstrating a notable increase in undetectable prostate-specific antigen (PSA) rates at 48 weeks. These findings, presented at the 2024 European Society for Medical Oncology (ESMO) Congress, suggest a potential new therapeutic avenue for this patient population.
Key Findings of the UpFrontPSMA Trial
The primary endpoint of the study, undetectable PSA (≤0.2 ng/mL) at 48 weeks, was achieved in 41% of patients in the lutetium-PSMA-617 plus docetaxel arm, compared to only 16% in the docetaxel-only arm (OR=3.88, 95% CI, 1.61-9.38, P = .002). This significant improvement underscores the potential of lutetium-PSMA-617 in achieving deeper PSA responses in mHSPC.
Several secondary endpoints also favored the experimental arm. Median PSA progression-free survival was 31 months in the lutetium-PSMA-617 arm versus 20 months in the docetaxel arm (HR=0.60, 95% CI, 0.37-0.98, P = .039). Additionally, the experimental arm had a median 20 months’ freedom from castration resistance (95% CI, 13-34) versus 16 months in the control arm (95% CI, 12-20) (HR=0.60, 95% CI, 0.38-0.96, P = .033).
Safety and Quality of Life
Importantly, the addition of lutetium-PSMA-617 did not increase overall toxicity. Grade 3-4 treatment-related adverse events were similar between the two arms (29% vs 27%). Quality of life and pain parameters were also comparable, indicating that the combination therapy did not negatively impact patients' well-being. The most common adverse event was dry mouth, which was more frequent in the lutetium-PSMA-617 arm, as expected.
Implications for Clinical Practice
These results are particularly significant given that the study focused on patients with de novo high-volume mHSPC, a subgroup known for poor prognosis. According to Dr. Azad, "UpFrontPSMA is the first randomized study in mHSPC to show a benefit from the addition of lutetium-PSMA to standard-of-care management." The findings suggest that lutetium-PSMA-617 could play a crucial role in improving outcomes for this challenging patient population.
Future Directions
While the UpFrontPSMA trial provides encouraging evidence, the field awaits the results of the Phase III PSMAddition trial, which is evaluating lutetium-PSMA-617 in combination with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). This trial will further clarify the utility of lutetium-PSMA-617 in the context of current standard-of-care treatments for mHSPC. As research progresses, a more personalized approach to managing mHSPC, incorporating lutetium-PSMA-617 for patients with high PSMA expression, may become a reality.
