Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer

Abstract

Background: Metastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (¹⁷⁷Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.

Methods: We conducted an international, open-label, phase 3 trial evaluating ¹⁷⁷Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (⁶⁸Ga)-labeled PSMA-11 positron-emission tomographic-computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (²²³Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.

Results: From June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. ¹⁷⁷Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). All the key secondary end points significantly favored ¹⁷⁷Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with ¹⁷⁷Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.

Conclusions: Radioligand therapy with ¹⁷⁷Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664.).

Figure 1. Screening, Randomization, and Follow-up of the Patients.

The numbers in parentheses indicate the numbers of patients who underwent randomization on or after March 5, 2019, which was the date on which trial‑site education measures were implemented to reduce the incidence of withdrawal from the trial in the control group (see the Supplementary Methods section). In the ¹⁷⁷Lu‑PSMA‑617 group, the reasons for withdrawal of consent to receive ¹⁷⁷Lu‑PSMA‑617 were the following: noted as “no reason given” on the case‑report form (in 1 patient), unknown (in 1), and treatment “fatigue” due to travel or protocol procedures (in 1). In the same group, the reasons for withdrawal of consent to receive standard care were the following: noted as “no reason given” on the case‑report form (in 1) and treatment “fatigue” due to travel or protocol procedures (in 1). In the control group, the reasons that patients withdrew consent to treatment were the following: an assessment that the patient was receiving best care without ¹⁷⁷Lu‑PSMA‑617 (in 31), noted as “no reason given” on the case‑report form (in 7), a decision to pursue treatment outside the trial (in 5), treatment “fatigue” due to travel or protocol procedures (in 2), and a perceived lack of benefit (in 1). CT denotes computed tomography, PET positron‑emission tomography, and PSMA prostate‑specific membrane antigen.

Figure 2. Imaging-based Progression-free Survival and Overall Survival (Primary Efficacy Outcomes) and Time to the First Symptomatic Skeletal Event (Key Secondary Outcome).

Panel A shows imaging‑based progression‑free survival among the 581 patients who had been randomly assigned to receive either ¹⁷⁷Lu‑PSMA‑617 plus standard care or standard care alone after the implementation of enhanced trial‑site education measures. Imaging‑based progression‑free survival, defined as the time to imaging‑documented disease progression according to criteria of the Prostate Cancer Clinical Trials Working Group 3 or death, was independently centrally reviewed. Panel B shows overall survival among all 831 patients who had undergone randomization. Panel C shows the time to first symptomatic skeletal event or death in the same population as was used in the analysis of imaging‑based progression‑free survival. Plus signs and circles indicate censored data in the ¹⁷⁷Lu‑PSMA‑617 group and control group, respectively; information on data censoring is provided in Table S5.