Professor Joe M. O’Sullivan MD FRCPI FFRRCSI FRCR
Chair of Radiation Oncology, Queen’s University Belfast
Consultant Clinical Oncologist, Northern Ireland Cancer Centre, Belfast.
Ionising radiation has been used as an effective cancer therapy for over 100 years. With the primary target of cancer cell DNA, most radiation therapy is delivered by linear accelerators in the form of external beam radiotherapy. An alternative way of administering therapeutic radiation to patients is to intravenously inject certain radioactive chemicals, known as radionuclides which can, by various means, gain close access to cancer cells and deliver ionising radiation at a molecular level as part of the radioactive decay process. Radionuclide therapy has been important in the treatment of metastatic prostate cancer for over 30 years, and a recently approved therapy, Lutetium-177- PSMA-617 (PLUVITCO ™, Novartis) has heralded a new and exciting era for the field.
Early Days of Radionuclide Therapy in prostate cancer
I first encountered the use of radionuclide therapy in advanced prostate cancer as a trainee radiation oncologist in St. Luke’s Hospital in Dublin back in the mid-1990’s. Patients with metastatic prostate cancer, no longer responding to castration therapy (the only life-prolonging systemic therapy available at the time), with severe uncontrolled bone pain, were referred for treatment with Strontium-89. It was my job as one of the trainee oncologists to assess the patient and then to inject the therapy as an intravenous bolus injection using a lead covered syringe. It is tough to think back on those men with advanced prostate cancer in severe pain, and without access to the multiple life-prolonging therapies now available to use in current practice.
Strontium-89 was the 1st radionuclide licensed for use in advanced prostate cancer. Strontium has very similar properties to calcium, and when injected intravenously as Strontium-89 Chloride, it will (like calcium) preferentially accumulate in mineral bone. This is useful in prostate cancer where bone is the dominant metastatic site, and the phenotype of the majority of bone metastases is ‘bone-forming’ or osteoblastic. These over-active areas of mineral bone adjacent to the metastatic deposits in the bone marrow ‘suck in’ the injected Strontium-89 which becomes incorporated into the hydroxyapatite of the mineral bone and allowing the delivery of ionising radiation.
In the case of Strontium-89, the radiation is in the form of beta-particles. These tiny ionising particles are similar to electrons and can travel over a radius of approximately 1-2 mm causing the formation of free radicals which in turn interact with cellular DNA. Around the same time as the emergence of Strontium-89 as a therapy in advanced prostate cancer, another beta-emitting radionuclide, Samarium-153 EDTMP was licensed. This radioisotope was not inherently bone-targeting but was made so by conjugation with a bisphosphonate (EDTMP).
Both Strontium-89 and Samarium-153 EDTMP were tested in multiple clinical trials in metastatic prostate cancer during the 1990’s. Most of these trials included relatively small numbers of patients with pain control/pain response as the primary endpoint. Prospective studies demonstrated a pain response rate in the order of 60-70%. It uncertain whether these therapies resulted in any meaningful alteration in the course of disease in these men. In particular, there was never any evidence of an overall survival benefit resulting from the use of these therapies, although none of the studies were properly powered to make that assessment .
Increasing the efficacy of Radionuclide therapy
During the early 2000’s there was considerable interest in enhancing the efficacy of radionuclide therapy in prostate cancer. Trials of Strontium-89 or Samarium-153 EDTMP combined with chemotherapy were conducted without much improvement in outcomes. The major challenge with dose intensification of radionuclide therapy is bone marrow toxicity. While working at Royal Marsden Hospital/Institute of Cancer Research I led a clinical research programme exploring the potential of dose escalation of Rhenium-186 HEDP (a beta-emitting bone-seeking radionuclide) in men with metastatic castration resistant prostate cancer (mCRPC) . The ambitious dose escalation scheme was facilitated by autologous peripheral blood stem cell transfusion. In an initial phase 1 dose escalation trial, we established a safe and tolerable administered activity of 5000MBq. Stem cells were mobilized using gCSF. We demonstrated excellent tolerability of the therapy and encouraging evidence of efficacy however the overall cost and resource usage of the procedure were ultimately prohibitive to further development.
In 2004, I was appointed to Queen’s University Belfast and continued my radionuclide research at the Northern Ireland Cancer Centre, Belfast. I developed a phase 1 trial explore the potential for combining repeated doses of Rhenium-186 HEDP with Docetaxel chemotherapy (The TAXIUM Trial) The study established a safe schedule of repeated Rhenium-186 HEDP combined with Docetaxel. I then developed a randomised phase 2 trial (The TAXIUM 2 Trial) which compared standard therapy with Cabazitaxel Chemotherapy and repeated Rhenium-188 HEDP. While well tolerated, the combination was not superior to Cabazitaxel alone .
The real game changer in the field of radionuclide therapy in advanced prostate cancer came in the form of Radium-223, developed in Oslo by Algeta and subsequently acquired by Bayer. Radium-223 is like Strontium-89, a calcium mimetic. The big difference is that Radium-223 decays by emitting Alpha particles (2 protons + 2 neutrons). These relatively massive (at an atomic level) entities cause massive DNA damage over a very short range (~100 microns) in tissue. The advantage of this short range of range of ionising radiation is the relative protection of the bone marrow and the potential to deliver the therapy in cycles akin to chemotherapy. The phase 3 ALSYMPCA trial demonstrated an overall survival advantage in metastatic castration resistant prostate cancer (mCRPC) over standard of care for 6 cycles of Radium-223 (XOFIGO ™) and the radionuclide became available for clinical use in 2013 . Radium-223 has been shown to be well tolerated in men with mCRPC and continues to be an important treatment option for men with castration resistant prostate cancer metastatic to bone.
Following the success of Radium-223 in mCRPC, I developed a phase 1/2 clinical trial which explored the role of Radium-223 in castration sensitive prostate cancer in combination with Androgen deprivation therapy, Docetaxel and external beam radiotherapy to the prostate and pelvic nodes. The ADRRAD trial finished recruitment in 2019 and published in 2021 establishing the safety and feasibility of this schedule. Several lines of parallel, translational science investigations from this study are now bearing fruit .
One of the major challenges with Radium-223 is that it only targets bone. While bone is the dominant site of spread in advanced prostate cancer, metastases are also commonly found in liver, lung and brain as well as lymph nodes. A new target was needed and a protein named Prostate Surface Membrane Antigen (PSMA), highly expressed in advanced prostate cancer, has proven to be an excellent candidate. The position of the PSMA molecule (Figure 1)  on prostate cells depends on the state of malignant transformation, being localized to the cytoplasmic and apical side of the prostate epithelium in benign cells and as malignancy evolves, PSMA moves from the cytoplasm to the luminal surface of the prostatic ducts, allowing the presentation of a large extracellular domain which is amenable to ligand binding. The normal role of PSMA is as yet uncertain however it appears likely to have a transport function across the cell membrane as PSMA ligands are internalized through endocytosis. One very important feature of the PSMA molecule is that expression generally increases with Gleason score, and as the patient progresses to metastatic castration-resistant prostate cancer (mCRPC). PSMA expression is not confined to prostate cells and can also in salivary glands, duodenal mucosa, proximal renal tubular cells, and neuroendocrine cells in the colon.
The PSMA molecule was first targeted by PET tracers enabling its use as a imaging tool with significantly improved sensitivity and specificity over conventional imaging such as isotope bone scan, CT, and MRI. Combining a therapeutic radionuclide (for example Lutetium-177) with a PSMA avid ligand (e.g. PSMA-617, a small molecule inhibitor of PSMA) opened the possibility of delivering ionising radiation directly to prostate cancer cells. This type of therapeutic approach is known as a radioligand therapy (RLT). Recent data on demonstrating overall survival benefit in mCRPC means that this agent will the 1st PSMA targeted radioligand available in the clinic.
177Lu-PSMA-617 (PLUVITCO ™)
Results of large international, industry sponsored randomised trial testing the benefit of 177Lu-PSMA-617, (The VISION Trial), have recently been published . In this trial, men with mCRPC who had prior therapy with at least one androgen-receptor–pathway inhibitor (e.g. Abiraterone, Enzalutamide) and (unless they were ineligible) at least one taxane (e.g. Docetaxel, Cabazitaxel) and with PSMA-positive metastases visible on a PSMA PET-CT scan (gallium-68 (68Ga)–labeled PSMA-11) were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus standard care (e.g. hormone therapy, local radiotherapy), or standard care alone. Standard care could not include cytotoxic chemotherapy, immunotherapy or other radionuclides including Radium-223.
In total, 831 patients were randomised. With a median follow-up of 20.9 months, patients randomised to receive 177Lu-PSMA-617 plus standard care were shown to have significantly prolonged radiographic progression free survival compared to the control arm (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40, P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; P<0.001) (Figure 2). All the key secondary end points were significantly in favour of 177Lu-PSMA-617. From the toxicity perspective, there were significantly more grade 3 or above adverse events (largely haematological) seen with 177Lu-PSMA-617 than in the control arm (52.7% vs. 38.0%), however quality of life did not appear to be adversely affected.
This study recruited patients in the 3rd line setting of mCRPC and a median survival of the patients in the control arm of just over 11 months is a good indicator of the advanced nature of the disease in this cohort of men.
177Lu-PSMA-617 has achieved regulatory approval in US and UK with EMA approval expected in the coming months and will join the armamentarium of available life-prolonging therapies in this space.
Implementing 177Lu-PSMA-617 will not be without its challenges including radioprotection, access to PSMA PET, and availability of a trained workforce in particular physicists and nuclear medicine technologists. Experience of using Radium-223 over the past 8 years will likely help many departments manage the new therapy.
As well as being used in earlier prostate cancer disease states, future directions for PSMA-targeted radionuclide therapy include the use of dosimetry to personalise the dose received by the patient, alternate radioisotopes in particular the alpha-emitters, Actinium-225 and Thorium-227, and combination with radiosensitisers. I believe it is a very exciting time for radionuclide therapy in cancer which will hopefully result in better outcomes for our patients.
- Brady D, Parker CC, O’Sullivan JM. Bone-targeting radiopharmaceuticals including radium-223. Cancer J. 2013 Jan-Feb;19(1):71-8. doi: 10.1097/PPO.0b013e318282479b. PMID: 23337760.
- O’Sullivan JM, McCready VR, Flux G, Norman AR, Buffa FM, Chittenden S, et al. High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone. Br J Cancer. 2002;86(11):1715-20.
- van Dodewaard-de Jong JM, de Klerk JM, Bloemendal HJ, van Bezooijen BP, de Haas MJ, Wilson RH, and O’Sullivan JM. A phase I study of combined docetaxel and repeated high activity 186Re-HEDP in castration-resistant prostate cancer (CRPC) metastatic to bone (the TAXIUM trial). Eur J Nucl Med Mol Imaging. 2011;38(11):1990-8.
- Parker C, Nilsson S, Heinrich D, O’Sullivan JM et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213-23.
- O’Driscoll et al, British J Pharmacol 2016, 173, 3041
- Turner PG, Jain S, Cole A, Grey A, Mitchell D, Prise KM, and O’Sullivan JM. Toxicity and Efficacy of Concurrent Androgen Deprivation Therapy, Pelvic Radiotherapy, and Radium-223 in Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer. Clin Cancer Res. 2021;27(16):4549-56.
- Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, Tagawa ST, Nordquist LT, Vaishampayan N, El-Haddad G, Park CH, Beer TM, Armour A, Pérez-Contreras WJ, DeSilvio M, Kpamegan E, Gericke G, Messmann RA, Morris MJ, Krause BJ; VISION Investigators. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Jun 23. doi: 10.1056/NEJMoa2107322.
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