Summary: Iodine-131 RPS-001 (also known as 131I-MIP-1095) is a novel radiolabelled small molecule targeting the prostate-specific membrane antigen (PSMA) receptor, offering a new therapeutic avenue for prostate cancer treatment. After a period of inactivity, clinical studies resumed in 2017, exploring its efficacy, particularly in combination with enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC). This article examines the development, mechanism of action, clinical trial progress, and future prospects of 131I-RPS-001 in prostate cancer therapy.
Introduction to 131I-RPS-001
Prostate cancer remains one of the most prevalent cancers among men worldwide. Despite advances in detection and treatment, metastatic castration-resistant prostate cancer (mCRPC) poses significant therapeutic challenges. The emergence of targeted therapies offers hope for improved outcomes. Among these, 131I-RPS-001 has garnered attention due to its specificity for PSMA, a protein abundantly expressed in prostate cancer cells.
Prostate-Specific Membrane Antigen (PSMA)
Structure and Function
PSMA is a type II transmembrane glycoprotein primarily expressed in the prostate epithelium. It has enzymatic functions, acting as a glutamate carboxypeptidase. While its physiological role in normal prostate tissue remains not fully understood, its overexpression in prostate cancer cells makes it an ideal target for diagnostic imaging and therapeutic interventions.
PSMA Expression in Other Cancers
Although predominantly associated with prostate tissue, PSMA expression has been observed in other solid tumours, including renal cell carcinoma and glioblastoma. However, the expression levels in these cancers are generally lower compared to prostate cancer, reinforcing the specificity of PSMA-targeted therapies for prostate malignancies.
131I-RPS-001: Molecular Characteristics
Chemical Composition
Iodine-131 RPS-001 is a small molecule analogue of glutamate-urea-lysine, radiolabelled with iodine-131. The molecule is designed to bind selectively to the PSMA receptor, allowing for targeted delivery of radiation to prostate cancer cells.
Mechanism of Action
Upon administration, 131I-RPS-001 binds to PSMA-expressing cells. The iodine-131 emits beta particles (β– radiation), causing DNA damage and cell death in the targeted cancer cells. This selective approach minimises exposure to surrounding healthy tissues, potentially reducing side effects compared to traditional radiotherapy.
Clinical Development
Initial Studies and Hiatus
Early clinical studies demonstrated the potential of 131I-RPS-001 in targeting PSMA-positive prostate cancer cells. However, development paused for seven years due to various factors, including strategic business decisions and the emergence of other therapeutic agents.
Resumption of Clinical Trials
In January 2017, clinical investigations of 131I-RPS-001 resumed. A Phase I study aimed to assess the safety, dosimetry, and preliminary efficacy of the molecule in patients with advanced prostate cancer. The study concluded in April 2019, providing encouraging results that warranted further exploration.
Phase II Clinical Trials
Combination with Enzalutamide
In June 2019, a Phase II clinical trial commenced to evaluate the efficacy of 131I-RPS-001 in combination with enzalutamide, an androgen receptor inhibitor commonly used in mCRPC treatment. The rationale behind this combination is to enhance therapeutic efficacy by attacking cancer cells through different mechanisms.
Study Objectives
- Primary Objective: Assess the safety and efficacy of the combination therapy.
- Secondary Objectives: Evaluate progression-free survival, overall survival, and quality of life metrics.
Patient Selection
Patients with confirmed mCRPC exhibiting PSMA-avidity, as determined by 18F-DCFPyL PET/CT imaging, were enrolled. PSMA-avidity ensures that the patients’ tumours express PSMA at levels sufficient for effective targeting by 131I-RPS-001.
Imaging and Assessment
18F-DCFPyL PET/CT imaging is utilised to assess PSMA expression in tumours. This imaging modality provides high sensitivity and specificity, aiding in patient selection and treatment monitoring.
Expected Outcomes and Completion
The trial aimed for completion by the end of 2022. While final results are pending, interim analyses suggest a favourable safety profile and potential efficacy, reinforcing the value of PSMA-targeted therapies in mCRPC.
Additional Phase II Study
Initiation and Objectives
Another Phase II study began in September 2019, projected to conclude by December 2024. This study focuses on assessing the therapeutic efficacy of 131I-RPS-001 as a monotherapy in patients with advanced prostate cancer.
Study Design
- Randomised Controlled Trial: Patients are randomised to receive either 131I-RPS-001 or standard of care.
- Endpoints: The primary endpoint is overall survival, with secondary endpoints including progression-free survival and tumour response rates.
Radiation Type and Safety Considerations
Beta Radiation (β– Electrons)
Iodine-131 emits beta particles, which have a relatively short range in tissue. This property allows for effective tumour irradiation while sparing adjacent normal tissues.
Safety Profile
Radiation safety is a critical aspect of radionuclide therapy. Patients receiving 131I-RPS-001 undergo monitoring for potential radiation-induced side effects, including marrow suppression and nephrotoxicity. To date, adverse events have been manageable, with protocols in place to mitigate risks.
Comparison with Other PSMA-Targeted Therapies
Emerging Radioligand Therapies
Other PSMA-targeted radioligand therapies, such as 177Lu-PSMA-617, have shown promising results in clinical trials. Comparing these agents is essential to determine the most effective and safe options for patients.
Advantages of 131I-RPS-001
- Higher Energy Emission: Iodine-131 emits higher energy beta particles compared to lutetium-177, potentially leading to increased tumour cell kill.
- Availability: Iodine-131 is widely available and cost-effective, which may facilitate broader access to treatment.
Future Directions
Personalised Medicine Approach
The utilisation of PSMA-targeted therapies aligns with the trend towards personalised medicine. By selecting patients based on PSMA expression, treatments can be tailored for maximum efficacy.
Combination Therapies
Ongoing research explores combining 131I-RPS-001 with other therapeutic agents, such as immunotherapies and chemotherapy, to enhance treatment outcomes.
Regulatory Considerations
Successful completion of clinical trials is necessary for regulatory approval. Continuous monitoring and reporting of trial results will inform decision-making by health authorities.
Conclusion
Iodine-131 RPS-001 represents a significant advancement in the treatment of prostate cancer. Its ability to specifically target PSMA-expressing cells offers a promising therapeutic option for patients with mCRPC. Clinical trials to date have demonstrated safety and potential efficacy, justifying further investigation. As research progresses, 131I-RPS-001 may become an integral part of prostate cancer management, improving survival and quality of life for patients.
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