Novel rhPSMA Therapy Targets Advanced Prostate Cancer With Precision

3D rendered medically accurate illustration of prostate cancer: © SciePro - stock.adobe.com

Lutetium (¹⁷⁷Lu) rhPSMA-10.1 injection, a radiopharmaceutical, demonstrated highly encouraging results in the phase 1 portion of a phase 1/2 clinical trial (NCT05413850) in patients with metastatic castration-resistant prostate cancer (mCRPC).¹

Results from this portion of the study, which included 13 patients with mCRPC, revealed significantly higher absorbed radiation doses in tumors compared with critical healthy tissues, such as the kidneys and salivary glands. Findings from the trial showed there to be a mean tumor-to-salivary gland ratio of 73 and a tumor-to-kidney ratio of 32 with the injection.

Additionally, the median absorbed radiation dose to tumors was 8.9 Gy per GBq of administered radioactivity, with mean doses of 0.27 Gy/GBq to the kidneys and 0.13 Gy/GBq to the salivary glands.

"The phase 1 data provides strong validation of the innovative approach taken on optimizing radioligand therapy by Blue Earth Therapeutics and the inventors of the rhPSMA technology. 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,” said David Gauden, DPhil, chief executive officer of Blue Earth Therapeutics, in a press release.

The mean biological half-life of ¹⁷⁷Lu-rhPSMA-10.1 in tumors was 338 hours. When combined with the 6.7-day physical half-life of ¹⁷⁷Lu-rhPSMA-10.1, this resulted in a mean half-life of 91.4 hours, an extended retention that allows for sustained radiation delivery to tumors over several days. This prolonged tumor exposure occurs without proportionate increases in healthy tissue retention, contributing to the ¹⁷⁷Lu-rhPSMA-10.1’s promising radiation dosimetry profile.

These results compare favorably to published data on first-generation PSMA-targeted radioligand therapies, suggesting a potentially improved therapeutic index.

About ¹⁷⁷Lu and the Phase 1/2 Trial

This international, non-randomized, open-label, phase 1/2 trial is currently evaluating the efficacy and safety of ¹⁷⁷Lu-rhPSMA-10.1 in patients with mCRPC.² The study consists of 2 parts. Part 1 includes safety, dose-finding and dosimetry components, while part 2 plans to assess efficacy and safety using the dose selected in phase 1.

The primary end points for phase 1 of the trial were dose-limiting toxicities and treatment-emergent adverse events. For phase 2, the primary end point is antitumor activity, as measured by the rate of patients reaching a ≥50% reduction in PSA level from baseline.²

The study plans to enroll approximately 150 patients and has a primary completion date of August 27, 2026.

Previous findings showed that the radiopharmaceutical ¹⁷⁷Lu-rhPSMA-10.1 led to positive initial efficacy and safety signals in this patient population.³ Data from an independent clinical experience of physicians at the University Hospital Augsburg, Germany, published in the Journal of Nuclear Medicine, showed that among 4 consecutive patients with mCRPC given ¹⁷⁷Lu-rhPSMA-10.1, progression-free survival (PFS) was not reached for 2 patients at 24 and 18 months of follow-up, respectively. The other 2 patients had a PFS period of 12 and 15 months, respectively.

Reductions in PSA levels from the start of treatment were seen among all 4 patients, including reductions of 100%, 99%, 88%, and 35%. One patient had a sustained complete response at 2 years of follow-up and no patients experienced a serious treatment-related adverse event.

Next Steps

Building on these positive phase 1 results, the phase 2 portion of the trial plans to evaluate innovative dosing regimens aimed at optimizing patient outcomes.¹ Following consultation with regulatory authorities, the phase 2 study will investigate the following:

• Administering significantly higher overall injected radioactivity compared with recent phase 3 trials of other PSMA-targeted therapies.
• Front-loading radioactivity in early treatment cycles to maximize initial tumor response.
• Extending the duration of treatment beyond 36 weeks to provide longer time on therapy.

The phase 2 part of the study is anticipated to begin this quarter.

“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 prostate cancer patients to benefit compared to available radioligand therapy, and completion of this study moves us closer to making that goal a reality," added Gauden in the press release.

REFERENCES:

1. Blue Earth Therapeutics reports key results from lutetium (177Lu) rhPSMA-10.1 injection phase 1 clinical trial. News release. March 13, 2025. Accessed March 13, 2025. https://tinyurl.com/2deunp4p

2. Dierks A, Gäble A, Rinscheid A, et al. First Safety and Efficacy Data with the Radiohybrid 177Lu-rhPSMA-10.1 for the Treatment of Metastatic Prostate Cancer. J Nucl Med. 2024;65(3):432-437. Published 2024 Mar 1. doi:10.2967/jnumed.123.266741

3. Anti-tumour activity of (177Lu) rhPSMA-10.1 injection. ClinicalTrials.gov. Updated November 22, 2024. Accessed March 13, 2025. https://clinicaltrials.gov/study/NCT05413850