177Lu-rhPSMA-10.1 injection shows positive radiation dosimetry results in mCRPC

Radiation dosimetry results from a phase 1 clinical trial (NCT05413850) of lutetium (¹⁷⁷Lu) rhPSMA-10.1 injection in patients with metastatic castration-resistant prostate cancer (mCRPC) showed proportionally higher absorbed radiation doses in tumors than in normal organs.¹

The phase 2 portion of the study is ongoing.

The data were presented at the 2025 Society of Nuclear Medicine and Molecular Imaging Annual Meeting in New Orleans, Louisiana. ¹⁷⁷Lu-rhPSMA-10.1 is a radiohybrid lutetium labelled, PSMA targeted, investigational radioligand therapy (RLT).

In total, the phase 1 study included 13 patients with mCRPC, of whom 3 received 5.55 GBq/cycle of ¹⁷⁷Lu-rhPSMA-10.1 and 10 received 7.40 GBq/cycle of ¹⁷⁷Lu-rhPSMA-10.1. Overall, the results demonstrated a favorable ratio between radiation doses absorbed in the tumor vs the doses delivered to key healthy organs, such as the kidneys and salivary glands.

Specifically, the mean tumor-to-kidney ratio was 32.09, and the mean tumor-to-salivary gland ratio was 73.19. The mean absorbed radiation dose to tumors was 8.87 Gy/GBq, compared with 0.30 Gy/GBq in the kidneys, 0.13 Gy/GBq in the salivary glands, and 0.01 in the bone marrow.

According to the authors, “Absorbed doses in other organs were in line with values reported previously for other PSMA RLT. Cumulative absorbed doses remained well below the limits applied in external beam radiotherapy.”

Data also showed a mean effective half-life of 2.2 h (SD, 0.5), confirming that ¹⁷⁷Lu-rhPSMA-10.1 was rapidly cleared from the blood.

An activity-based tumor dosimetry evaluation was then conducted in a total of 36 lesions, of which 27 were in the bone and 9 were in the lymphatic sites. In this analysis, the mean tumor absorbed dose was 8.9 Gy/GBq (range, 2.3 to 25.7), resulting in a mean tumor-to-kidney (T:K) ratio of 32 and a mean tumor-to-salivary (T:S) gland ratio of 73.

The investigators then conducted an anatomy-based dosimetry evaluation using tumor volumes defined only on CT scan by a blinded radiologist (n = 57 lesions). According to Blue Earth Therapeutics, this captures “all regions of the tumor irrespective of uptake of the drug.” This analysis led to lower tumor dose estimates, with T:K and T:S ratios of 9 and 19, respectively.

Data also showed that tumor absorbed doses decreased with each cycle.

According to the authors, “[The] decline in tumor absorbed dose with subsequent cycles suggests that a fixed dosing regimen may not be optimal for PSMA RLT; higher cumulative absorbed tumor dose can be achieved by administering a higher proportion of radioactivity during earlier cycles.”

The investigators plan to explore the efficacy and safety of this approach in phase 2 of the trial.

"Numerous studies across various cancer types have shown the therapeutic value of delivering high radiation doses to tumors. At the same time, due to the risk of normal organ toxicity, one cannot simply administer unlimited amounts of radioactivity to patients,” explained David Gauden DPhil, CEO of Blue Earth Therapeutics, in a news release from the company.² “The solution is to develop therapeutic agents that improve the tumor:normal organ ratios so that the proportion of injected radioactivity reaching the tumors is scaled up to maximize efficacy. The phase 1 dosimetry data being presented here at SNMMI is an important validation of the concept that improved agents are possible.”

Phase 2 of the Study

The phase 2 portion of the phase 1/2 study is currently ongoing. According to Blue Earth, the phase 2 portion is assessing:

• “Administration of significantly higher overall injected radioactivity in comparison 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.”³

Patients are being enrolled in the trial through clinical trial sites in the US and the Netherlands.⁴

The study will include patients whose tumors have progressed on or after at least 1 novel androgen axis drug (abiraterone acetate [Zytiga], enzalutamide [Xtandi], apalutamide [Erleada], or darolutamide [Nubeqa]) but have not received previous taxane-based chemotherapy. Additionally, to be eligible for enrollment, patients must have a serum testosterone level below 50 ng/dL, an ECOG performance score of 0 to 2, a life expectancy of at least 6 months, and adequate bone marrow reserve and organ function, among other measures.

Participants will be randomly assigned to 1 of 3 cohorts. In cohort 2A, patients will receive 2 doses of ¹⁷⁷Lu-rhPSMA-10.1 at 10.00 GBq followed by up to 5 additional doses at 7.40 GBq, with all doses administered at 6-weekly intervals. In cohort 2B, patients will receive up to 8 doses of ¹⁷⁷Lu-rhPSMA-10.1 at 7.40 GBq, with the first 3 administered at 3-weekly intervals and the rest at 6-weekly intervals. In cohort 2C, patients will receive 2 doses of ¹⁷⁷Lu-rhPSMA-10.1 at 14.80 GBq followed by up to 4 additional doses at 7.40 GBq, with all doses administered at 6-weekly intervals.

The primary outcome measure is the number of patients with an anti-tumor response, defined as at least a 50% reduction in prostate-specific antigen from baseline.

Gauden concluded, “We look forward to the clinical efficacy results from the ongoing phase 2 portion of the trial. In this phase, we may begin to see benefits driven by the unique properties of the rhPSMA molecule. Additionally, the novel dosing regimen, which is designed to deliver higher cumulative doses of radioactivity with front-loading in the early treatment cycles, could provide further therapeutic advantage."

Primary completion of the trial is expected in August 2026.

REFERENCES

1. Organ and tumor dosimetry of a novel PSMA-targeted radioligand therapy 177Lu-rhPSMA-10.1: Results from a phase 1 study. Presented at: Society of Nuclear Medicine and Molecular Imaging Annual Meeting. June 21-24, 2025. New Orleans, Louisiana. https://www.xcdsystem.com/snmmi/program/B95p18u/index.cfm?pgid=2402&sid=46736&abid=146032

2. Blue Earth Therapeutics: SNMMI presentation of results from lutetium (177Lu) rhPSMA-10.1 injection phase 1 clinical trial. News release. Blue Earth Therapeutics Ltd. June 25, 2025. Accessed June 26, 2025. https://4078578.fs1.hubspotusercontent-na1.net/hubfs/4078578/Lutetium%20rhPSMA%20Phase%201%20SNMMI%202025_press%20release.docx.pdf

3. Blue Earth Therapeutics reports key results from lutetium (177Lu) rhPSMA-10.1 injection phase 1 clinical trial. News release. Blue Earth Therapeutics Ltd. March 13, 2025. Accessed June 26, 2025. https://4078578.fs1.hubspotusercontent-na1.net/hubfs/4078578/BET%20Headline%20Results%20Phase%201%20Final.pdf

4. Anti-tumour activity of (177Lu) RhPSMA-10.1 injection. ClinicalTrials.gov. Last updated March 20, 2025. Accessed June 26, 2025. https://clinicaltrials.gov/study/NCT05413850