UpFrontPSMA: 177Lu-PSMA-617 shows potential in mHSPC

The combination of 177Lu-PSMA-617 (lutetium Lu 177 vipivotide tetraxetan; Pluvicto) with docetaxel improved outcomes in patients metastatic hormone-sensitive prostate cancer (mHSPC) without an increase in toxicity vs docetaxel alone, according to results from the phase 2 UpFrontPSMA (NCT04343885).

The findings were presented at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain and published in The Lancet Oncology.^1,2

Arun Azad, MBBS, PhD

“UpFrontPSMA is the first randomized study of lutetium-PSMA in mHSPC,” said study author Arun Azad, MBBS, PhD, a urologic oncologist at Peter MacCallum Cancer Centre and an associate professor at the University of Melbourne in Australia.

“Lutetium-PSMA is approved and recommended for metastatic castration-resistant prostate cancer.^3,4 But its utility in metastatic hormone-sensitive disease, until now, has been unknown. The landmark CHAARTED trial [NCT00309985] established ADT plus docetaxel as a standard of care for de novo, high-volume mHSPC,⁵ but outcomes for this patient population remain poor. We hypothesized that the addition of lutetium-PSMA to docetaxel would improve clinical outcomes in this patient group without increasing toxicity,” Azad said in his presentation.

Patients were eligible for the study if they had metastatic prostate adenocarcinoma that had been diagnosed within the past 12 weeks, and had received 4 weeks or less of ADT.

“Eligible patients on PSMA-PET had high PSMA uptake and high disease volume, with no major discordance on FDG-PET,” Azad said.

Patients were randomly assigned 1:1 to either the experimental arm, consisting of 2 cycles of 177Lu-PSMA-617 followed by 6 cycles of docetaxel, or the control arm, consisting of 6 cycles of docetaxel, 75 mg/m2. The primary end point was undetectable prostate-specific antigen (PSA) level at 48 weeks. This was defined as a PSA level of 0.2 ng/mL or lower. Secondary end points included PSA progression-free survival (PFS), castration resistance, radiographic PFS, overall survival, quality of life and pain, and adverse events (AEs).

The investigators initially chose a sample size of 140 patients to provide 85% power; however, “Accrual was stopped at 130 patients due to delays in recruitment caused by COVID-19-related lockdowns in Australia in 2020 and 2021,” the authors wrote. Ultimately, power was reduced to 82% with 130 patients. Recruitment took place between May 5, 2020 and April 18, 2023 at 11 Australian centers. Median follow-up was 2.5 years (IQR, 1.8-3.0 years). A total of 63 patients were randomly assigned to the experimental arm vs 67 in the control arm.

“All patients randomized to the experimental arm received both cycles of lutetium-PSMA as planned, with no dose reductions and only 1 dose delay,” Azad said. Twenty-one (33%) patients in the experimental arm had dose reduction of docetaxel vs 11 (17%) patients in the control arm. In addition, 6 (10%) patients in the experimental arm discontinued docetaxel due to toxicity vs 4 (6%) patients in the control arm. A total of 50 (79%) patients in the experimental arm and 53 (84%) patients in the control arm completed all 6 cycles of docetaxel.

Patient characteristics were well balanced between the experimental and control arms. Number of patients with T3-T4 disease was 38 (67%) in the experimental arm vs 45 (75%) in the control arm. In addition, 48 (89%) patients in the experimental arm had Grade Group 4-5 disease vs 51 (92%) patients in the control arm, and 60 (95%) patients in the experimental arm had high-volume disease on conventional imaging vs 55 (87%) in the control arm.

“The primary end point of this study was clearly met,” Azad said. In the experimental arm, 41% of patients (95% CI, 30%-54%) had an undetectable PSA level at week 48 vs 16% (95% CI, 9%-28%) in the control arm (OR=3.88; 95% CI, 1.61-9.38, P = .002).

Median PSA PFS was 31 months (95% CI, 14-NE) in the experimental arm vs 20 months (95% CI, 14-23) (HR=0.60; 95% CI, 0.37-0.98, P = .039). In the experimental arm, the experimental arm had a median 20 months’ freedom from castration resistance (95% CI, 13-34) vs 16 months in patients (95% CI, 12-20) in the control arm (HR=0.60; 95% CI, 0.38-0.96, P = .033).

Median rPFS was not estimable in the experimental arm compared with 22 months (95% CI, 17-28) in the control arm (HR=0.58; 95% CI, 0.32-1.05, P = .067).

“Quality of life and pain parameters were generally similar between the treatment arms,” Azad said.

Regarding AEs, 70% of patients in the experimental arm had any treatment-related grade 1-2 AE vs 71% of patients in the control arm. Grade 3-4 treatment-related AEs were experienced by 29% of patients in the experimental arm vs 27% of patients in the control arm.

“UpFrontPSMA is the first randomized study in mHSPC to show a benefit from the addition of lutetium-PSMA to standard-of-care management. In patients with de novo, high-volume mHSPC, the addition of lutetium-PSMA to docetaxel compared to docetaxel alone significantly improved the primary end point of undetectable PSA at 48 weeks and improved multiple secondary end points with no increase in overall toxicity. Collectively, these data indicate that lutetium-PSMA has a potential role in the therapeutic management of mHSPC. The phase 3 PSMAddition trial will further inform the utility of lutetium-PSMA in patients with metastatic hormone-sensitive prostate cancer,” Azad concluded.

REFERENCES

1. Azad AA, Tan H, Voskoboynik M, et al. UpFrontPSMA: A randomised phase II study of sequential 177Lu-PSMA-617 and docetaxel (D) versus docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC). Presented at: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract LBA66. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2024_abstracts/LBA66.html.pdf

2. Sequential [177Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study. Lancet Oncol. Published online ahead of print September 15, 2024. Accessed September 16, 2024. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00440-6/abstract?rss=yes

3. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322

4. Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804. doi:10.1016/S0140-6736(21)00237-3

5. Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747