LuPSMA May Improve Survival in Heavily Pretreated mCRPC

The novel targeted radiation therapy lutetium-177 PSMA-617 showed strong clinical activity and the potential to improve survival in heavily pretreated men with PSMA-positive metastatic castration-resistant prostate cancer.

Michael S. Hofman, MBBS

The novel targeted radiation therapy lutetium-177 PSMA-617 (LuPSMA) showed strong clinical activity and the potential to improve survival in heavily pretreated men with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).1

Among 50 patients receiving LuPSMA in a single-arm, single center phase II trial, 32 (64%; 95% CI, 50-77) had a PSA decline ≥50%, with 22 (44%; 95% CI, 30-59) having a decline ≥80%. The median overall survival (OS) was 13.3 months (95% CI, 10.5-18.0), an improvement over historical data showing anywhere from a 6 to 9 month average survival time in this patient population.

“These results in 50 men provide further confidence to our previously published 30-patient cohort,2 demonstrating high response rates and low toxicity in men with mCRPC who progressed after multiple conventional therapies,” lead study author Michael Hofman, MBBS, a professor of nuclear medicine at the Peter MacCallum Cancer Centre, said when presenting the data on a presscast held in advance of the 2019 Genitourinary Cancers Symposium.

Explaining the study rationale, Hofman said, “PSMA is overexpressed 100 to 1000 times in prostate cancers, with expression further increased in metastatic and castration-resistant carcinomas,” adding, “Lutetium-177 (177Lu)-PSMA-617 is a radiolabeled small molecule that binds with high affinity to PSMA enabling tumor-targeted delivery of beta-radiation.”

For the phase II study, investigators at the Peter MacCallum Cancer Centre screened 76 patients using PSMA/FDG PET, with 16 patients subsequently being excluded for insufficient PSMA uptake. The median patient age was 71 (range, 50-87) for the 50 patients who went on to receive LuPSMA. The median PSA was 190 and the median PSA doubling time was 2.6 months. Ninety percent of patients had received abiraterone acetate (Zytiga), enzalutamide (Xtandi), or both; 84% had prior docetaxel; and 48% had received cabazitaxel (Jevtana).

“Many of these men had no further treatment options and without this study, they probably would have received end-of-life palliative care,” said Hofman. “These patients were very sick when they came. The majority of these patients had pain from the spread of their cancer—usually to the bones, so they were on opiate or morphine analgesia to control that. And their performance status was often reduced—they weren’t able to do the things they were normally able to do.”

Under the study design, patients received 4 intravenous cycles of LuPSMA in an outpatient setting every 6 weeks. The median number of treatment cycles was 4, with 8 patients receiving <4 cycles following an exceptional response. Additionally, disease progression led to 10 patients not finishing all planned cycles.

Beyond the 32 patients with a PSA decline ≥50%, an additional 5 patients had a PSA decline ≥30%. Overall, the median interval in which patients did not have a PSA increase was 6.9 months.

There were only 2 patients in whom there was no PSA reduction. “We think this is probably a feature of our careful selection of patients with the PET scanning upfront to really enrich the study for patients who were likely to benefit from the treatment,” said Hofman.

The median OS was significantly longer among patients with a greater PSA decline. The median OS was 18.0 versus 8.7 months among patients with a PSA decline of ≥50% versus <50%, respectively (P = .001).

There were 14 patients who responded but subsequently progressed who then received further LuPSMA treatment after study completion as part of an off-trial expanded access program. In this group, 64% of patients had a PSA decline ≥50% and the median OS was 33 months.

The most common grade 1/2 treatment-related adverse events (TRAEs) were dry mouth (68%), nausea (48%), and fatigue (36%). The most frequent grade 3/4 TRAEs were thrombocytopenia and anemia, each occurring in 10% of patients.

“Survival rates are low for patients with prostate cancer that has spread to distant parts of the body, and providing effective treatments for this type of cancer has been an ongoing challenge for physicians. For this group of patients in dire need of new options, using an entirely new approach, this study provides hope that we can start to change their outcomes,” ASCO expert Robert Dreicer, MD, MS, MACP, FASCO, moderator of the presscast, said in a statement.

Hofman said results from this trial supported the launch of randomized studies of LuPSMA. The phase II TheraP trial (NCT03392428) is comparing LuPSMA with cabazitaxel in men with PSMA-positive, progressive mCRPC. The phase III VISION trial (NCT03511664) is evaluating LuPSMA versus best standard of care in men with PSMA-positive, progressive mCRPC.


  1. Hofman M, Violet JA, Hicks RJ, et al. Results of a 50 patient single-centre phase II prospective trial of Lutetium-177 PSMA-617 theranostics in metastatic castrate-resistant prostate cancer. J Clin Oncol. 2019;37 (suppl; abstr 228).
  2. Hofman MS, Violet J, Hicks RJ, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19(6):825-833. doi: 10.1016/S1470-2045(18)30198-0.

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