Jan. 20, 2024
Mayo Clinic researchers found that lutetium-177 (177Lu)-PSMA-617 prolonged radiographic progression-free survival (rPFS) in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who were taxane-naive and had progressive disease after receiving androgen receptor pathway inhibition (ARPI) therapy compared with those who received a second ARPI therapy. These phase 3 PSMAfore clinical trial findings were presented at the European Society for Medical Oncology (ESMO) Congress in October 2023.
"The study was significantly positive for radiographic progression-free survival, along with a variety of secondary endpoints, and lutetium was very well tolerated," says Alton O. Sartor, M.D., a medical oncologist, the chair of the Genitourinary Cancer Disease Group, and the director of Radiopharmaceutical Clinical Trials at Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota. "We look forward to a future where lutetium may be a viable therapy for patients in need of alternative, earlier options," says Dr. Sartor.
The transforming landscape of metastatic prostate cancer treatment
Recent advancements in diagnostic techniques and new treatment modalities have improved the five-year survival rate for metastatic prostate cancer to 32%. Mayo Clinic has been instrumental in this progress, particularly through its early adoption, broad use and skilled interpretation of PSMA PET scans. These scans are more sensitive than traditional bone and CT scans, providing a more comprehensive and accurate diagnosis and thereby enhancing disease management.
Novel hormonal therapies such as abiraterone and enzalutamide and the pioneering use of radiopharmaceuticals such as 177Lu-PSMA-617 have reshaped the therapeutic landscape, increasing treatment options for patients. Mayo Clinic's multidisciplinary prostate cancer team has been at the forefront of offering these new options to patients with metastatic prostate cancer, administering the highest volume of 177Lu-PSMA-617 globally.
The integration of molecular imaging and targeted precision therapies, along with a deeper understanding of cancer genetics in conjunction with radiopharmaceuticals, immunotherapies, new treatments and innovative combinations of these treatments, is providing a new level of hope for patients with metastatic prostate cancer.
Phase 3 PSMAfore trial results
This phase 3 trial focused on patients with PSMA PET-positive mCRPC who had not received taxane-based chemotherapy and had progressive disease after ARPI therapy. Patients were randomized to receive either 177Lu-PSMA-617 every six weeks or a second ARPI therapy. Lutetium met its primary endpoint with a statistically significant benefit in rPFS (12 months) compared with ARPI (5.59 months), with a hazard ratio of 0.43. This result and positive secondary endpoints indicate a robust treatment effect.
"We are working toward changing the treatment paradigm for advanced prostate cancer by allowing patients to potentially receive lutetium-177 prior to taxane-based chemotherapy. This is particularly important given that many patients with prostate cancer have difficulty with the side effects of chemotherapy."
Patients whose cancer continued to progress with ARPI were allowed to cross over to 177Lu-PSMA-617, and 84% of patients chose this option. The high crossover rate influenced post-rPFS endpoints, including overall survival, and complicated the interpretation of overall survival (OS) data. An adjusted analysis showed a hazard ratio of 0.80, while the intent-to-treat analysis was 1.16. Researchers plan to continue evaluating OS, with the next interim OS analysis expected in 2024.
Use of 177Lu-PSMA-617 was well tolerated with fewer severe adverse events and dose adjustments needed, compared with ARPI. Patients treated with 177Lu-PSMA-617 had a more effective reduction in prostate-specific antigen and an improved quality of life.
Radiopharmaceuticals are currently restricted to patients who have progressed after hormone therapies and taxane chemotherapy. "We are working toward changing the treatment paradigm for advanced prostate cancer by allowing patients to potentially receive lutetium-177 prior to taxane-based chemotherapy. This is particularly important given that many patients with prostate cancer have difficulty with the side effects of chemotherapy," says Dr. Sartor.
The future of metastatic prostate cancer treatment
Research is ongoing to explore PSMA-based theranostics' role in the treatment of prostate cancer. In addition to 177Lu-PSMA-617, clinical trials are ongoing for 177Lu-PNT2002 and 177Lu-PSMA-I&T. Early research is promising for actinium-255, an alpha emitter, which has different benefits compared with beta emitters such as lutetium. PSMA-antibody-drug conjugates are another treatment modality with active and encouraging research.
"Metastatic prostate cancer is undergoing a promising shift," says Dr. Sartor. Research in this space is abundant and is moving the field forward with the goals of expanding treatment options and improving patient outcomes.
Dr. Sartor emphasizes the critical role of advanced diagnostics, novel therapies, and a multidisciplinary team approach including experts in medical oncology, nuclear medicine, radiation oncology and urology. Mayo Clinic is at the forefront of novel therapies in metastatic prostate cancer, pushing the boundaries of treatment and offering new hope for patients.
For more information
Sartor AO, et al. LBA13 phase III trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Annals of Oncology. 2023;34(suppl2):S1324
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