Radioligand therapy for advanced prostate cancer patients – We need to boost our health care systems

In December 2022 the radiopharmaceutical ¹⁷⁷Lu-PSMA-617, labelled with the beta-particle emitter ¹⁷⁷Lu (lutetium), obtained marketing authorisation in the EU for the treatment of metastatic castration resistant prostate cancer¹. This radiopharmaceutical targets the Prostate Specific Membrane Antigen (PSMA), which is overexpressed on the cancer cells in about 80% of the patients suffering from advanced prostate cancer. These 80% of patients are identified using a companion diagnostic product targeting the same PSMA, radiolabelled with the positron-emitter ⁶⁸Ga (gallium). 

This allows imaging and quantifying the density of the PSMA targets on the patients’ cancer by Positron Emission Tomography (PET/CT). This approach is frequently referred to as (radio)theranostics because diagnosis and therapy use exactly the same targets on the cancer cells. Therefore this therapy is a truly personalised method of precision oncology because the patents are selected based on the individual molecular profile of their cancer. The molecule PSMA-617 brings the beta-particle-emitter ¹⁷⁷Lu to the cancer cells and kills them with the locally released beta-radiation. The beta-particles have a range of a couple of millimetres in tissue. Thus, they perform their cell-killing task locally and spare healthy tissue. 

The radiopharmaceutical is injected intravenously and localises rapidly on tumour cells in the whole body binding to the PSMA on their surface. In this way advanced stage patients, which frequently have even hundreds of metastasis all over the body can benefit from this treatment. The injection is repeated up to six times in a distance of six weeks and is usually well tolerated. The treatment has less side effects and they are usually of a temporary nature and easier to manage than those of conventional therapies. Therefore, patients report a significantly better quality of life as they have experienced with the hormone and chemotherapies they underwent before. Most patients will be able to pursue their normal daily activities. Therapy with ¹⁷⁷Lu-PSMA-617 extends progression free survival significantly, improves overall survival and above all improves the quality of life in the time the patients gain. 

The current, first marketing authorisation restricts the application of ¹⁷⁷Lu-PSMA-617 to patients which have progressing disease after Androgen Deprivation Therapy (ADT) of castration sensitive prostate cancer and after chemotherapy of castration resistant cancer when patients no longer respond to ADT. Clinical trials are under way with the goal to bring the ¹⁷⁷Lu-treatment to patients earlier in the course of disease, i.e, before chemotherapy and, ideally, before hormone deprivation therapy with all its side effects, which drastically reduce patients’quality of life. 

Since still about one third of the patients currently treated with ¹⁷⁷Lu-PSMA-617 do not even respond to this therapy, other clinical trials investigate the simultaneous combination of this treatment with hormone and chemotherapies². The hope is to find combination treatments, which do better than the individual treatments alone. Another approach to overcome the resistance of cancer to beta-radiation observed in patients treated with ¹⁷⁷Lu is to substitute it with the alpha-particle emitter ²²⁵Ac (actinium). The results obtained so far indicate that the largest part of patients with progressing disease under ¹⁷⁷Lu treatment can be brought back into response with ²²⁵Ac-PSMA-617 therapy³.

Encouraged by such results, industry is currently investing significantly in boosting the production capacities⁴ for the so far rare radionuclide ²²⁵Ac. The promising clinical trials with ¹⁷⁷Lu-PSMA-617 and ²²⁵Ac-PSMA-617 give further hope for future advanced-stage prostate cancer patients, which may be treated earlier and more efficiently. However, this goes along with a further increase of the number of eligible patients and with a shift of cancer treatment from classical oncology towards nuclear medicine. But European health care systems are not yet prepared for such a development. 

The successful introduction of a targeted molecular radiotherapy against gastroentero-pancreatic neuroendocrine tumours (GEP NETs)⁵ using ¹⁷⁷Lu-DOTATATE (marketing authorisation in EU in 2017) happened rather unobserved since these cancers are rare. The situation is now completely different since prostate cancer has a much higher incidence. For the expected high number of eligible prostate cancer patients the currently existing treatment capacity will no longer be sufficient⁶. The number of beds in nuclear medicine therapy wards with adequate radiation protection equipment and facilities to treat radioactive waste also from patient excretions must be increased. In addition, a more sophisticated look at radiation protection procedures is required to use the scarce hospital resources more efficiently. 

Moreover, the expected high number of eligible patients will require more medical doctors specialised in PET/CT or PET/MRI imaging, in the administration of radiopharmaceuticals as well as skilled nursing staff, medical physicists and radiation protection operators⁷. Decision makers in public and private health care need to be aware of the dimension of the problem and must take the proper decisions to overcome the bottleneck of equipment and staffing.

A further issue is the reimbursement of the therapy. While the marketing authorisation is valid for the whole EU, reimbursement decisions are a prerogative of the Member States and even in some Member States, decisions are taken in federal structures or by different health care payers. This takes time, a time patients do not have. Currently, in the US investments go into treatment capacities and the most important health care payers have approved reimbursement for the indications authorised by the FDA. This has led to a shift of research and investments from Europe to the US where decisions are taken faster and revenue is more certain and immediate. However, molecular radiotherapies with 177Lu-DOTATATE and ¹⁷⁷Lu-PSMA-617 are European developments, and Europe had the technology leadership in this field for about 30 years. Now, therapies are refined and further molecular radiotherapies against other types of cancer are developed and made available to patients on large scale elsewhere.

The EU has adopted Europe’s Beating Cancer Plan and the Cancer Mission with the goal is to improve “the lives of more than 3 million people by 2030 through prevention, cure, and for those affected by cancer including their families, to live longer and better"⁸. It should be our European ambition to unfold the full potential of targeted molecular radiotherapies to achieve this goal. The JRC is supporting this by disseminating information and data to increase the awareness among decision makers in policy and health care systems. Moreover, the JRC is actively involved in the clinical development and testing of ²²⁵Ac-PSMA-617 in prostate cancer patients⁹. In order to provide current and future cancer patients access to these innovative treatments and to integrate them into clinical practice European health care systems require a boost.

Uwe HOLZWARTH, JRC - Joint Research Centre

References

¹ https://www.ema.europa.eu/en/medicines/human/EPAR/pluvicto

² Jadvar and Colletti, Journal of Nuclear Medicine Technology March 2023, 51 (1) 16-21; DOI: https://doi.org/10.2967/jnmt.122.264928

³ E.g.: Kratochwil et al., Journal of Nuclear Medicine December 2016, 57 (12) 1941-1944; DOI: https://doi.org/10.2967/jnumed.116.178673

⁴ Journal of Nuclear Medicine October 2023, 64 (10) 1516-1518; DOI: https://doi.org/10.2967/jnumed.123.265907

⁵ https://www.ema.europa.eu/en/medicines/human/EPAR/lutathera

⁶ https://publications.jrc.ec.europa.eu/repository/handle/JRC134480

⁷ HEALTH TECHNOLOGY ASSESSMENT: 177Lu-PSMA-617 for treatment of metastatic castration resistant prostate cancer (pdf)

⁸ https://research-and-innovation.ec.europa.eu/funding/funding-opportunities/funding-programmes-and-open-calls/horizon-europe/eu-missions-horizon-europe/eu-mission-cancer_en

⁹ Sathekge et al., Lancet Oncol 2024; 25: 175–83; Online January 10, 2024 https://doi.org/10.1016/S1470-2045(23)00638-1