Targeting Metastatic Castration Resistant Prostate Cancer: The Promising Role of Lutetium-177 labelled PSMA Radioligand Therapy

Prostate cancer remains one of the leading causes of cancer-related death among men worldwide. Although numerous advances in treatment options, metastatic castration resistant prostate cancer (mCRPC) remains a clinical challenge, often requiring aggressive and innovative approaches for effective management. Recently, targeted radioligand therapy utilising lutetium-177-labelled prostate-specific membrane antigen (¹⁷⁷Lu-PSMA) has emerged as a promising treatment for mCRPC patients, demonstrating significant clinical benefit and an acceptable safety profile.

¹⁷⁷Lu-PSMA: A Novel Radioligand Therapy

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein highly overexpressed in prostate cancer cells. This characteristic has made PSMA an attractive target for targeted cancer therapies, particularly in the management of mCRPC. Lutetium-177 is a beta-emitting radionuclide that delivers cytotoxic radiation directly to tumour cells when bound to a PSMA-targeting ligand. By targeting PSMA-expressing cells, ¹⁷⁷Lu-PSMA therapy selectively delivers radiation to cancerous cells while sparing healthy tissues, minimising the risk of side effects.

Clinical Evidence for ¹⁷⁷Lu-PSMA in mCRPC

Several clinical trials have investigated the safety and efficacy of ¹⁷⁷Lu-PSMA therapy in mCRPC patients. For example, a landmark phase 2 trial demonstrated that ¹⁷⁷Lu-PSMA-617 significantly reduced prostate-specific antigen (PSA) levels in mCRPC patients who had exhausted other treatment options.

The study reported a 50% or greater reduction in PSA levels in 57% of patients, with a median progression-free survival (PFS) of 7.6 months and overall survival (OS) of 13.5 months. The treatment was generally well-tolerated, with the most common side effects being fatigue, nausea, and transient thrombocytopenia.

Building on these positive results, the phase 3 VISION trial (2021) confirmed the clinical benefits of ¹⁷⁷Lu-PSMA-617 in mCRPC patients who had previously received at least one androgen receptor pathway inhibitor and taxane-based chemotherapy.

The trial reported a significant improvement in PFS and OS for patients receiving ¹⁷⁷Lu-PSMA-617 in combination with standard of care compared to those receiving standard of care alone (median PFS: 8.7 months vs 3.4 months; median OS: 15.3 months vs 11.3 months). However, treatment-related adverse events were consistent with previous studies, with the most common side effects being fatigue, anaemia, and thrombocytopenia.

Extended Treatment with ¹⁷⁷Lu-PSMA

As the clinical evidence supporting the use of ¹⁷⁷Lu-PSMA in mCRPC patients grows, researchers have begun to explore the potential benefits of extended treatment with this novel radioligand therapy. Preliminary data from ongoing studies suggest that patients may derive additional benefits from receiving more than the standard four cycles of ¹⁷⁷Lu-PSMA-617. For example, a recent retrospective analysis demonstrated that mCRPC patients who received more than four cycles of ¹⁷⁷Lu-PSMA-617 experienced a significantly longer median OS than those who received four or fewer cycles (22.0 months vs 12.0 months).

However, balancing extended treatment’s potential benefits with cumulative toxicity risks is important. The safety profile of extended ¹⁷⁷Lu-PSMA treatment remains relatively unexplored, and limited data is available on the long-term effects of repeated cycles. While the existing clinical trials indicate an acceptable safety profile for ¹⁷⁷Lu-PSMA therapy, further research is needed to understand extended treatment’s tolerability better and identify potential dose-limiting toxicities.

Strategies to Optimise ¹⁷⁷Lu-PSMA Therapy

To maximise the therapeutic potential of ¹⁷⁷Lu-PSMA in mCRPC patients, several strategies are being investigated to optimise treatment outcomes and minimise adverse events. These strategies include:

• Identifying patients most likely to benefit from ¹⁷⁷Lu-PSMA therapy is crucial for optimising treatment outcomes. Therefore, PSMA expression levels, prior treatment history, and overall health should be considered when selecting patients for this therapy.
• Combining ¹⁷⁷Lu-PSMA with other therapies, such as androgen receptor pathway inhibitors or immune checkpoint inhibitors, may improve treatment outcomes by targeting cancer cells through multiple mechanisms. Clinical trials are currently underway to assess the safety and efficacy of these combination approaches.
• Using radioprotective agents, such as amifostine, may help reduce the risk of treatment-related toxicities in patients undergoing ¹⁷⁷Lu-PSMA therapy. However, more research is needed to determine the most effective radioprotective agents and to establish optimal dosing regimens.
• By using personalised dosimetry, clinicians can tailor the administered activity of ¹⁷⁷Lu-PSMA to each patient’s individual needs, potentially maximising treatment efficacy while minimising the risk of toxicities.

Conclusion

¹⁷⁷Lu-PSMA therapy has demonstrated significant clinical benefits for patients with metastatic castration resistant prostate cancer, offering a new treatment option for those who have exhausted other therapies. As the evidence supporting using ¹⁷⁷Lu-PSMA grows, extended treatment regimens may provide additional benefits for select patients. However, further research is needed to fully understand the safety and tolerability of extended treatment and optimise treatment strategies for this promising therapy. Through ongoing clinical trials and translational research, ¹⁷⁷Lu-PSMA has the potential to significantly improve the management of metastatic castration resistant prostate cancer, offering hope for patients and their families.

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