In an Australian phase II trial (UpFrontPSMA) reported in The Lancet Oncology, Azad et al found that sequential lutetium (Lu)-177–prostate-specific membrane antigen (PSM)-617 (Lu-177–PSMA-617) and docetaxel was superior to docetaxel alone in achieving undetectable prostate-specific antigen (PSA) levels in patients with de novo high-volume metastatic hormone-sensitive prostate cancer.
Study Details
In the multicenter open-label trial, 122 evaluable patients were randomly assigned between May 2020 and April 2023 to receive two cycles of Lu-177–PSMA-617 at 7.5 GBq every 6 weeks followed 6 weeks later by six cycles of docetaxel at 75 mg/m2 every 3 weeks (n = 61) or six cycles of docetaxel at the same dosage (n = 61). All patients received continuous androgen-deprivation therapy. Patients had high-volume PSMA-avid disease on gallium Ga-68–PSMA-11 positron-emission tomography/computed tomography (PET-CT) and no major discordance on 2-[18F] fluorodeoxyglucose PET-CT and had up to 4 weeks on androgen-deprivation therapy prior to randomization. The primary outcome measure was undetectable PSA (≤ 0.2 ng/mL) at 48 weeks.
Undetectable PSA
Median follow-up was 2.5 years (interquartile range = 1.8–3.0 years). Undetectable PSA at 48 weeks was achieved in 25 of 61 patients (41%, 95% confidence interval [CI] = 30%–54%) given Lu-177–PSMA-617 plus docetaxel vs 10 of 61 patients (16%, 95% CI = 9%–28%) given docetaxel alone (odds ratio [OR] = 3.88, 95% CI = 1.61–9.38, P = .0020). Undetectable PSA at any time was observed in 51% vs 32% of patients (OR = 2.14, 95% CI = 1.03–4.46, P = .042).
KEY POINTS
- Sequential Lu-177–PSMA-617 and docetaxel produced a higher rate of undetectable PSA vs docetaxel alone in patients with de novo, high-volume, metastatic hormone-sensitive prostate cancer.
- Sequential Lu-177–PSMA-617 and docetaxel was associated with prolonged PSA progression-free survival compared with docetaxel alone.
Median PSA progression-free survival was 31 months (95% CI =14 months to not reached) with Lu-177–PSMA-617 plus docetaxel vs 20 months (95% CI = 14–23 months) with docetaxel alone (hazard ratio = 0.60, 95% CI = 0.37–0.98, P = .039.
Adverse Events
Among 63 patients in each group who received at least one dose of study drugs, grade 3 or 4 treatment-related adverse events occurred in 29% of those given Lu-177–PSMA-617 plus docetaxel vs 27% of those given docetaxel alone; the most common adverse events were febrile neutropenia (11%) and diarrhea (6%) in the Lu-177–PSMA-617–plus-docetaxel group and febrile neutropenia (10%) in the docetaxel group (no others > 3%). Serious adverse events occurred in 25% of each group. Adverse events led to discontinuation of treatment in 10% vs 6% of patients. No treatment-related deaths were reported.
The investigators concluded: “[Lu-177–PSMA-617] followed by docetaxel improved antitumor activity in patients with de novo high-volume metastatic hormone-sensitive prostate cancer compared with docetaxel alone, without increased toxic effects. Our data potentially support a role for [Lu-177–PSMA-617] in metastatic hormone-sensitive prostate cancer.”
Arun A. Azad, PhD, of the Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, is the corresponding author of The Lancet Oncology article.
Disclosure: The study was funded by the Prostate Cancer Research Alliance (Movember Foundation and Australian Government Medical Research Future Fund), Endocyte/Advanced Accelerator Applications (a Novartis company), and others. For full disclosures of the study authors, visit thelancet.com.
