177Lu rhPSMA-10.1 Injection in mCRPC
| Image Credit: © Sebastian Kaulitzki
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Treatment with the radiohybrid, PSMA-targeted, radioligand therapy Lutetium (177Lu) rhPSMA-10.1 injection led to proportionally higher absorbed radiation doses in tumors compared with healthy tissues in 13 patients with metastatic castration-resistant prostate cancer (mCRPC), according to dosimetry and pharmacokinetic data from the phase 1 portion of a phase 1/2 trial (NCT05413850).1
Results indicated that the 177Lu rhPSMA-10.1 injection has high ratios for the absorbed radiation dose to tumors vs that to healthy tissues, with a measured mean tumor-to-salivary gland ratio of 73 and tumor-to-kidney ratio of 32. The median absorbed radiation dose to tumors, which was defined by SPECT imaging, was 8.9 Gy for each GBq of radioactivity that was delivered. The mean absorbed radiation dose was 0.27 Gy/GBq to the kidneys and 0.13 Gy/GBq to salivary glands.
“The phase 1 data provide strong validation of the innovative approach taken on optimizing radioligand therapy by Blue Earth Therapeutics and the inventors of the rhPSMA technology,” David Gauden, DPhil, chief executive officer of Blue Earth Therapeutics, the developer of the agent, said in a news release.
rhPSMA compounds are known as radiohybrid because each molecule is composed of 4 different domains. The first is a PSMA-targeted receptor ligand, which is attached to 2 labelling moieties that can be radiolabeled with diagnostic isotopes, such as Fludeoxyglucose-18 or Gallium-68 for PET imaging, or with therapeutic isotopes, such as 177Lu or Actinium-225 for radioligand therapy.
In 2022, the FDA cleared an investigational new drug application for 177Lu-rhPSMA-10.1 as a potential therapeutic option for patients with mCRPC, allowing the initiation of the present phase 1/2 study.2
Further results from the trial indicated that the mean biological half-life in tumors for the 177Lu rhPSMA-10.1 injection was 338 hours.1 Coupled with the 6.7-day physical half-life of 177Lu, the effective mean half-life was 91.4 hours, allowing radiation to be administered over the course of several days. Blue Earth Therapeutics noted that the extended retention of the drug in tumors without proportionate increases to retention in normal tissues supports the positive radiation dosimetry data.
“The relative ratios of tumor to healthy organ absorbed radiation doses are key metrics in establishing a better profile of the risks and potential benefits of radioligand therapies,” Gauden continued in the news release. “With radioligand therapies, normal organ toxicity considerations gate the total amount of radioactivity that can be administered, so the more of the radioactivity that accumulates in tumors, the better. Our goal is to substantially increase the potential for [patients with] prostate cancer to benefit compared to available radioligand therapy, and completion of this study moves us closer to making that goal a reality.”
To be eligible for enrollment in the study, patients needed to be at least 18 years of age with histologically confirmed adenocarcinoma of the prostate.3 Additional criteria included serum testosterone levels below 50 ng/dL after surgical or continued chemical castration; the presence of target or non-target lesions per RECIST 1.1 criteria on CT/MRI and full body 99mTc bone scan within 28 days of screening; positive PSMA expression as confirmed on PSMA PET/CT scan; and at least 4 weeks or 5 half-lives between the last anticancer treatment and the start of study treatment.
Based on these findings, the company is expected to launch the phase 2 portion of the trial, where investigators will examine innovative dosing regimens.1 The specific focus of the trial will be 3-fold: to test the administration of significantly higher overall injected radioactivity relative to recent phase 3 clinical trials of other PSMA-targeted radioligand therapies; front loading of administered radioactivity in early cycles; and extending the duration of administration of radioactivity beyond 36 weeks to provide longer time on treatment. The phase 2 portion of the trial is expected to start in the first quarter of 2025.
The primary end point of phase 2 will be antitumor response as measured by at least a 50% reduction in prostate-specific antigen level from baseline.3
References
Blue Earth Therapeutics reports key results from Lutetium (177Lu) rhPSMA-10.1 injection phase 1 clinical trial. News release. Blue Earth Therapeutics. March 13, 2025. Accessed March 13, 2025. https://www.prnewswire.com/news-releases/blue-earth-therapeutics-reports-key-results-from-lutetium-177lu-rhpsma-10-1-injection-phase-1-clinical-trial-302400601.html
Blue Earth Therapeutics announces US FDA clearance for investigational new drug (IND) application for 177Lu-rhPSMA-10.1 for treatment of prostate cancer. News release. Blue Earth Therapeutics; April 12, 2022. Accessed March 13, 2025. https://4078578.fs1.hubspotusercontent-na1.net/hubfs/4078578/BET%20Phase%201%20IND%20press%20release%20final%20for%20April%2012%202022-1.pdf
Anti-tumor activity of (177Lu) RhPSMA-10.1 injection. Clinicaltrials.gov. Updated November 22, 2024. Accessed March 13, 2025. https://clinicaltrials.gov/study/NCT05413850