The FDA approval of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) has marked a significant advancement in the treatment of prostate cancer, particularly for patients with metastatic castration-resistant prostate cancer (mCRPC). This radioligand therapy targets the prostate-specific membrane antigen (PSMA), offering a novel mechanism of action for patients who have progressed on other anticancer therapies. The integration of lutetium Lu 177 vipivotide tetraxetan highlights the potential of radioligands in earlier settings and as part of combination therapies.
Impact on mCRPC Treatment Paradigm
Lutetium Lu 177 vipivotide tetraxetan has shown significant benefits in prolonging overall survival (OS) and improving the quality of life for patients with pretreated, PSMA-positive mCRPC. Data from the phase 3 VISION trial supported the FDA approval, demonstrating that the benefits seen in the clinical trial translated into real-world practice. Many patients have experienced substantial treatment breaks after completing the therapy, a notable improvement in a disease state where continuous treatment was the norm.
Expanding Access and Improving Patient Care
Over the past two years, the availability and accessibility of lutetium Lu 177 vipivotide tetraxetan have increased, with more community centers offering the treatment. Effective communication between radiation oncologists, nuclear medicine doctors, and medical oncologists is crucial for managing patient care. Assessing response beyond prostate-specific antigen (PSA) levels, including the use of serial PET scans, can aid in treatment decisions and optimize patient outcomes.
Potential for Earlier Use and Combination Therapies
There is growing interest in using lutetium Lu 177 vipivotide tetraxetan earlier in the disease course, potentially leading to deeper and more durable responses. The phase 3 PSMAddition trial is evaluating the combination of lutetium Lu 177 vipivotide tetraxetan with standard-of-care androgen receptor pathway inhibitors (ARPIs) in the metastatic hormone-sensitive setting. This approach aims to leverage the synergy between radioligand therapy and hormonal therapies to improve patient outcomes.
Novel Strategies and Future Directions
Researchers are exploring new strategies to improve treatment options for patients with mCRPC, including the development of AR degraders and proteolysis-targeting chimera (PROTAC) approaches. Targeting EZH2 and other epigenetic mechanisms may also offer promising avenues for controlling AR expression. Additionally, rechallenging patients with ARPIs after disease progression remains a viable option, with ongoing research focused on identifying biomarkers to guide treatment decisions.
Radium-223 and PEACE-3 Trial
The phase 3 PEACE-3 study demonstrated that the combination of enzalutamide and Radium-223 improved median OS by more than 7 months in patients with first-line mCRPC who had not received prior ARPIs. This clinically substantial benefit suggests that Radium-223 can uniquely alter the metastatic tumor volume, offering a breakthrough in frontline mCRPC treatment.
PSMAfore Trial
Data from the phase 3 PSMAfore study have generated significant interest in using 177Lu-PSMA-617 before chemotherapy in mCRPC. The trial demonstrated superior radiographic progression-free survival (rPFS) compared to ARPI switch, along with improvements in overall response rate and quality of life. The agent also significantly prolonged time to symptomatic skeletal events versus ARPI change.
Addressing Unmet Needs and Exploring New Targets
Despite the advances with lutetium Lu 177 vipivotide tetraxetan, many patients do not respond or relapse during treatment, highlighting the need for better strategies. Researchers are exploring radiopharmaceuticals based on alpha emitters and other targets beyond PSMA, such as hK2, DLL3, and the STEAP gene family. These efforts aim to provide more effective and personalized treatment options for patients with advanced prostate cancer.
