177Lu-PSMA-617 Receives FDA Breakthrough Therapy Designation for mCRPC


The FDA granted a breakthrough therapy designation to 177Lu-PSMA-617 for the treatment of patients with metastatic castration-resistant prostate cancer.

The FDA granted a breakthrough therapy designation to 177Lu-PSMA-617 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).1

The designation is supported by data from the phase 3 VISION trial (NCT03511664), in which the investigational radioligand therapy was found to improve radiologic progression-free survival (rPFS) and to prolong overall survival (OS) over standard-of-care (SOC) treatment alone in patients with advanced-stage prostate-specific membrane antigen (PSMA)–positive mCRPC.2

At a median follow-up of 20.9 months, the addition of 177Lu-PSMA-617 to SOC resulted in a median OS of 15.3 months vs 11.3 months with SOC alone among all randomized patients (n = 831; HR, 0.62; 95% CI, 0.52-0.74; P <.001). Among the rPFS analysis set (n = 581), the addition of the radioligand therapy to SOC also resulted in a 5.3-month improvement in median rPFS over SOC alone, at 8.7 months and 3.4 months, respectively (HR, 0.40; 99.2% CI, 0.29-0.57; P <.001).

A total of 831 patients were included in the open-label phase 3 trial. To be eligible for enrollment, patients needed to have previously received both at least 1 androgen receptor pathway inhibitor and 1 or 2 taxane regimens, an ECOG performance status of 0 to 2, and a life expectancy of over 6 months. Patients needed to be PSMA positive on PET/CT with 68Ga-PSMA-11. Protocol-permitted SOC had to have been planned prior to randomization.

Study participants were randomized 2:1 to either protocol-permitted SOC plus the radioligand therapy given at 7.4 GBq (200 mCi) every 6 weeks for 4 cycles, which was increasable to 6 cycles (n = 551); or protocol-permitted SOC alone (n = 280). Although investigators chose the SOC, radium-223 (Xofigo) and cytotoxic chemotherapy were not permitted.

Patients were stratified by ECOG performance status (0 to 1 vs 2), lactate dehydrogenase (high vs low), liver metastases (yes vs no), and androgen receptor pathway inhibitors in SOC (yes vs no). The co-primary end points of the trial were OS and rPFS.

A statistically significant benefit favored the radioligand therapy arm for important secondary end points of objective response rate (ORR), disease control rate (DCR), and time to first symptomatic skeletal event (SSE).

The ORR experienced in the investigative arm was 29.8% vs 1.7% in the control arm; the DCR was 89.0% vs 66.7%, respectively. Moreover, the median time to first SSE was 11.5 months and 6.80 months in the investigative and control arms, respectively (HR, 0.50).

A total of 529 patients in the 177Lu-PSMA-617 cohort and 205 in the SOC-alone cohort were included in the safety analysis. The radioligand therapy was determined to be well tolerated. The most frequent toxicities reported in the investigative vs control arms included fatigue (49.1% vs 29.3%, respectively), bone marrow suppression (47.4% vs 17.6%), dry mouth (39.3% vs 1%), nausea/vomiting (39.3% vs 17.1%), kidney effects (8.7% vs 5.9%), second primary malignancies (2.1% vs 1%), and intracranial bleeding (1.3% vs 1.5%).

High-grade treatment-emergent adverse effects (AEs) were reported in 52.7% of patients who received the radioligand therapy vs 38.0% of those who were given SOC alone. The most frequent grade 3 to 5 AEs experienced in the investigative arm comprised bone marrow suppression (23.4%), fatigue (7%), kidney effects (3.4%), and nausea/vomiting (1.5%).

Two ongoing studies are examining 177Lu-PSMA-617 in earlier lines of treatment for patients with metastatic prostate cancer. Specifically, efforts are being made to evaluate the potential for the therapy in patients with mCRPC in the pre-taxane setting, as well as in the metastatic hormone-sensitive setting.


  1. Novartis receives FDA breakthrough designation for investigational 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC). News release. Novartis. June 16, 2021. Accessed June 17, 2021. https://bit.ly/35w0wOu
  2. Morris MJ, De Bono JS, Chi KN, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(suppl 15):LBA4. doi:10.1200/JCO.2021.39.15_suppl.LBA4
Related Videos
Jun Gong, MD
Neal Shore, MD, FACS
Neal Shore, MD, FACS,
Samuel U. Takvorian, MD, MS
Jun Gong, MD
Janaki Neela Sharma, MD