Lu-177 Vipivotide in Prostate Cancer: A Breakthrough in Radioligand Therapy

Abstract

Prostate cancer continues to be a major cause of cancer death in men, and castration-resistant prostate cancer (CRPC) is a major therapeutic challenge. Lutetium Lu-177 vipivotide tetraxetan, a radioligand therapy directed against prostate-specific membrane antigen (PSMA), is a promising option for CRPC patients who have progressed after androgen receptor pathway inhibitors (ARPIs) and taxane-based chemotherapy. Current clinical trials have assessed its safety profile and efficacy in taxane-naïve patients, with favorable progression-free survival (PFS) compared to other ARPI switching approaches, although benefits on overall survival (OS) are unclear. The clinical value of Lutetium Lu-177 vipivotide tetraxetan, its action mechanism, and its possible role in the CRPC treatment algorithm are reviewed herein.

Introduction

Prostate cancer is among the most frequently diagnosed cancers in men, and although androgen deprivation therapy (ADT) is initially successful, numerous patients ultimately acquire castration-resistant prostate cancer (CRPC). The introduction of androgen receptor pathway inhibitors (ARPIs) like enzalutamide and abiraterone has enhanced outcomes, but resistance to these treatments inevitably occurs. For those patients who respond to ARPIs, taxane chemotherapy is still the standard of care, but its toxicity profile restricts tolerability in most patients. Lutetium Lu-177 vipivotide tetraxetan, a targeted radioligand therapy, has been considered a new treatment option. This article summarizes its place in CRPC management, such as clinical efficacy, safety, and its possible use before taxane chemotherapy.

Mechanism of Action

Lutetium Lu-177 vipivotide tetraxetan is a PSMA-targeting radioligand therapy (RLT) that preferentially binds to the overexpressed prostate-specific membrane antigen in CRPC cells. After binding, localized radiation is delivered by the beta-emitting Lutetium-177, causing DNA damage and apoptosis to cancer cells while leaving normal tissues unaffected. Such targeted therapy increases efficacy with decreased systemic toxicity over conventional chemotherapy.

Clinical Trials and Efficacy

Lutetium Lu-177 Vipivotide Tetraxetan after ARPI Failure

The VISION trial was a landmark Phase III trial that assessed Lutetium Lu-177 vipivotide tetraxetan in CRPC patients who had failed one or more ARPIs and taxane chemotherapy. The trial proved the treatment with an increase in overall survival (OS) and progression-free survival (PFS) to gain FDA approval for use in this population of patients. Nonetheless, interest developed in finding out if the treatment could be as effective earlier in the course, before chemotherapy.

Lutetium Lu-177 Vipivotide Tetraxetan in Taxane-Naïve Patients

A randomized clinical trial involving over 400 patients with PSMA-positive CRPC, who had progressed on an ARPI but were taxane-naïve, evaluated Lutetium Lu-177 vipivotide tetraxetan versus switching to an alternative ARPI. The results demonstrated a median PFS of 12 months for Lutetium Lu-177 vipivotide tetraxetan compared to 5.6 months for the ARPI switch. However, the OS benefit did not reach statistical significance, highlighting the need for further investigation into optimal patient selection and combination strategies.

Safety and Adverse Events

Lutetium Lu-177 vipivotide tetraxetan has shown a favorable safety profile relative to chemotherapy. In the taxane-naïve study, the incidence of grade ≥3 adverse events was lower in the Lutetium Lu-177 vipivotide tetraxetan group (36%) compared to those continuing ARPI therapy (48%). Common adverse effects include:

• Hematologic Toxicity: Mild to moderate anemia, leukopenia, and thrombocytopenia are common but generally manageable.

• Gastrointestinal Effects: Nausea, dry mouth, and mild diarrhea may occur but are less severe than those seen with chemotherapy.

• Renal Toxicity: Though uncommon, renal function should be monitored due to potential radiation-induced nephrotoxicity.

Mitigation strategies, including dose modifications and supportive care, are essential to optimize patient outcomes while minimizing toxicity.

Comparison with Existing Therapies

Current treatment options for CRPC include ARPIs, chemotherapy, and bone-targeting agents such as radium-223. Compared to chemotherapy, Lutetium Lu-177 vipivotide tetraxetan offers:

• Better Tolerability: Lower incidence of severe toxicities compared to taxane chemotherapy.

• Targeted Action: Selectively delivers radiation to PSMA-positive cells, reducing systemic side effects.

• Improved PFS: Superior disease control compared to sequential ARPI use.

However, the lack of a confirmed OS benefit in taxane-naïve patients underscores the need for further research.

Future Directions and Challenges

Regulatory Approval and Clinical Implementation

While Lutetium Lu-177 vipivotide tetraxetan is approved for use after both ARPI and taxane failure, its role before taxane chemotherapy awaits regulatory approval. The ongoing PRINCE trial and similar studies will further clarify its positioning in the treatment sequence.

Combination Strategies

Given its targeted nature, combining Lutetium Lu-177 vipivotide tetraxetan with other therapies may enhance efficacy. Potential strategies include:

• Combining with ARPIs: To maintain androgen signaling suppression while delivering targeted radiation.

• Dual Radioligand Therapy: Exploring synergy with alpha-emitting radiopharmaceuticals like actinium-225.

• Immunotherapy Integration: Investigating potential immune-enhancing effects of radiation-induced tumor cell death.

Optimizing Patient Selection

Not all CRPC patients express high PSMA levels, and PSMA imaging with PET-CT is crucial for selecting candidates who will benefit most. Future research aims to refine biomarker-driven selection criteria to personalize therapy.

Conclusion

Lutetium Lu-177 vipivotide tetraxetan is a new paradigm in the management of CRPC, and it provides an option for patients who have already progressed on ARPIs. Although existing evidence favors its application after taxane, new findings indicate benefits also in taxane-naïve patients. The trials ongoing now will establish if it can be used earlier in the treatment timeline. Additional study of combination regimens, biomarker-based selection, and late-term outcomes will further define its place in CRPC treatment, ultimately enhancing patient survival and well-being.

Read more such content on @ Hidoc Dr | Medical Learning App for Doctors