Radionuclide therapies are gaining traction as a viable treatment option for advanced prostate cancer, particularly in cases where patients have developed resistance to conventional treatments like androgen deprivation therapy and taxane-based chemotherapy. These therapies offer a targeted approach, delivering radiation directly to cancer cells while minimizing damage to surrounding healthy tissue.
Radionuclide Therapy in Prostate Cancer
In nuclear medicine, radiolabeling allows visualization of molecular targets. When targets are sufficiently expressed, the same probes may be radiolabeled with particle-emitting radioisotopes, delivering higher energy to eradicate tumor cells. This strategy is referred to as a theragnostic approach. Several radiolabeled probes directed against PSMA have been designed for imaging and therapy over the last decades.
Radium-223: Targeting Bone Metastases
Radium-223 dichloride (Xofigo) was the first radionuclide therapy to demonstrate an overall survival benefit in patients with metastatic castration-resistant prostate cancer (mCRPC). The ALSYMPCA clinical trial reported a median overall survival of 14.9 months in patients treated with Radium-223 compared to 11.3 months in the placebo group (HR = 0.7, 95% CI 0.58–0.83, p < 0.001). Radium-223, an alpha-emitting radionuclide, targets bone metastases due to its affinity for osteoblasts.
Lutetium-177 PSMA-617: A Targeted Approach
More recently, Lutetium-177 PSMA-617 (Lu-PSMA-617) has shown promising results. The VISION clinical trial, a phase III randomized study, compared standard of care (SoC) alone or in combination with Lu-PSMA-617 in mCRPC patients. The study found a significant benefit in terms of radiological progression-free survival (8.7 vs. 3.4 months; HR = 0.40; p < 0.001) and overall survival (15.3 vs. 11.3 months; HR = 0.62, p < 0.001) in favor of Lu-PSMA-617 plus SoC.
Ongoing Clinical Trials and Combination Therapies
Several ongoing clinical trials are exploring the use of Lu-PSMA-617 in earlier stages of prostate cancer and in combination with other therapies. These include studies in metastatic hormone-sensitive prostate cancer (mHSPC) and investigations into combining Lu-PSMA-617 with androgen deprivation therapy, external beam radiation therapy, and immunotherapy.
Actinium-225 PSMA Ligands: A Promising Alternative
Targeted alpha therapy involving Actinium-225 (Ac-225)-labeled PSMA ligands is emerging as a potential alternative, particularly for patients who do not respond to Lu-177 based treatments. Early studies have shown impressive biological and radiological responses with Ac-225 PSMA-617, even in clinically critical situations.
Clinical Management and Considerations
Based on the results of the VISION clinical trial, the FDA approved lutetium-177 vipivotide tetraxetan (Lu-PSMA-617) (Pluvicto) for the treatment of patients with PSMA-positive mCRPC who have undergone treatment with inhibitors of the androgen axis and taxane-based chemotherapy. PSMA-positive mCRPC patients are defined as having at least one tumor lesion with a 68Ga-PSMA-11 uptake greater than normal liver. Common adverse reactions include fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. Patients should be monitored for toxicity every 3 weeks, including hematological surveillance and kidney function evaluation.
Future Directions
Research is ongoing to explore new therapeutic radioisotopes, vector molecules targeting PSMA, and alternative targets for prostate cancer radionuclide therapy. These efforts aim to improve treatment outcomes and expand the applicability of radionuclide therapy to a broader range of patients.
