A new treatment protocol for determining effective therapies with a reduced number of side effects may soon be an option for patients with advanced prostate cancer.

German researchers have developed a dosing regimen for actinium-225-labeled targeted alpha therapy protocol, which balances response to treatment and toxicity concerns to find the most effective therapy with the least number of side effects for advanced-stage, metastatic castration-resistant prostate (mCRPC) cancer patients with prostate-specific membrane antigen (PSMA)-positive tumors. Their findings were compiled in a study that was published in the October issue of The Journal of Nuclear Medicine.

“Most of the approved hormone therapy drugs are targeting the androgen-receptor,” Clemens Kratochwil, a senior physician in the department of nuclear medicine at University Hospital Heidelberg and one of the authors of the study, told HCB News. “Sharing the same target structure increases the risk for cross-resistance when given consecutively. Targeting the PSMA-receptor is complementary. There are also other PSMA-targeting approaches, such as conjugates of PSMA-antibodies and chemotherapeutics. These drugs are facing the inherent resistance of prostate cancer against most conventional chemotherapy. In contrast, radiotherapy is a standard modality for treatment of localized prostate cancer. This is an indicator that prostate cancer is often sufficiently radiosensitive.”

Therapy options for advanced-stage mCRPC are limited, and though the idea of a targeted alpha therapy is not new, clinical experience is also limited. The study demonstrates how preclinical knowledge can be applied to humans.

Researchers calculated a dosimetry estimate based on time-activity curves acquired from serially obtained PET/CT scans extrapolated to the physical half-life life of actinium-225, assuming instant decay of unstable daughter nuclides. Fourteen patients underwent salvage therapies with four receiving 50 kBq/kg of actinium-225-PSMA-617, four receiving 100, two receiving 150 and four receiving 200. Eight of the 14 underwent further cycles in two or four month intervals with identical or deescalated activities.

Salvage therapy results found that patients can tolerate 100 kBq/kg of actinium-225-PSMA-617 and that it showed potential in anti-tumor response. Researchers also found that repeated treatments over the course of eight weeks may allow for continual tumor control.

Kratochwil says that phase three clinical trials could take years and that supply limitations have still not been solved, but that the protocol holds potential to become a standard resource in the future.

“Once the supply limitations of Ac-225 will be solved, we can expect that prospective multicenter trials will be started to evaluate the impact of this therapy on patient survival,” he said. “As we observed remarkable anti-tumor activity with regard to radiological or biochemical surrogate response-markers, it would be a surprise if these trials would not demonstrate efficacy. Thus, the probability that we will see PSMA-TAT as a standard option for advanced prostate cancer is high.”

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