Dr. de Bono notes that the categorization of targeted alpha therapies is by method of delivery, specifically:
- Mechanism mediated targeted alpha therapy (eg. radium-223), which selectively targets tumor cells in specific organs/tissues based on inherent chemical properties. Radium-223 is a calcium mimetic that selectively binds to areas of increased bone turnover, including bone metastases. Importantly, <2% of radium-223 alpha-emitting radionuclides migrate away from the bone surface, which helps with minimizing off-target exposure. Radium-223 has a dual mode of action, working to incorporate into the tumor microenvironment to inhibit tumor growth, and to suppress tumor-induced abnormal bone formation.
- Monoclonal antibody-mediating targeted alpha therapy (eg. anti-CD22-thorium-227), which uses conjugation to monoclonal antibodies or antibody fragments that target tumor cells. This binding is with very high affinity, and coupled with a high molecular weight and Fc region, this prolongs serum half-life from days to weeks.
- Peptide-or small-molecule-mediated targeted alpha therapy (eg. actinium-225-PSMA-617), which uses conjugation to small molecules or peptides to target tumor cells. These molecules may include ligands, synthetic protein scaffolds (eg. affibodies), and substrate analogs (eg. peptides).
This flexibility of targeting mechanisms allows for a wide range of applicability across tumor types. Specific to prostate cancer, these include radium-223, thorium-227, and actinium-225.
As has been well documented in the ALSYMPCA trial , radium-223 resulted in a 30% reduction in risk of death compared with placebo in men with mCRPC, as well as significantly improving all secondary efficacy endpoints. In a recent study, radium-223 continues to demonstrate low myelosuppression incidence with no new safety concerns three years after first injection . This included no acute myeloid leukemia, myelodysplastic syndrome, or new primary bone cancer.
There continues to be ongoing clinical trials examining radium-223 in combination with novel anti-hormonal agents. The PEACE III trial is assessing radium-223 + enzalutamide vs enzalutamide monotherapy, with a primary endpoint of radiographic PFS and overall survival (OS) as a secondary endpoint. The target sample size is 560 men, with key criteria being no second-generation ADT, no prior chemotherapy, and patients must be asymptomatic/mildly symptomatic. The second trial is the ERA 223 trial assessing radium-223 + abiraterone vs abiraterone monotherapy. The primary endpoint is symptomatic skeletal event-free survival and secondary endpoints will include radiographic PFS and OS. The target sample size is 806 men, with key criteria being no prior chemotherapy for CRPC, and patients must be asymptomatic/mildly symptomatic.
Further interest includes combination of immune-oncology agents with ionizing radiation, considering tumor cell death and secretion of signaling molecules by irradiation-stressed cells in the microenvironment promote immune cell activation. Furthermore, radium-223 incorporation and alpha-particle emission impact both osteoblasts and osteoclasts resulting in immunogenic response. Secondly, there is interest in comparing DNA repair inhibition and targeted alpha therapy. Inhibiting DNA repair will increase cell kill by decreasing rescue of double-strand DNA breaks. There are currently multiple agents in clinical development in this space, including PARP inhibitors and other drugs targeting ATR, ATM, and DNA-PK. Certainly, the concern is that adding targeted alpha therapy may increase anti-tumor activity/efficacy, but could result in increased toxicity.
There are several emerging agents in targeted alpha therapy. Targeted thorium conjugates are being investigated in several tumor types, including prostate cancer. Secondly, actinium-225-PSMA-617 has been investigated in mCRPC patients having been used off-trial through compassionate access programs. In early investigations, two patients achieved a complete response on imaging and no hematologic toxicity reported, although six patients (43%) had grade 1 xerostomia and two patients (14%) had grade 2 xerostomia.
Dr. de Bono concluded with a number of key points, including (i) targeted alpha therapy delivers high, localized energy that is lethal to cancer cells but minimizes damage to nearby health tissue, (ii) there is broad applicability across tumor types, and (iii) there are attractive combination choices with a range of current and emerging therapies including immunotherapy, DNA repair inhibitors, and hormonal therapy.
Speaker: Johann de Bono, Institute of Cancer Research and Royal Marsden, London, United Kingdom
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
1) Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-223.
2) Parker CC, Coleman RE, Sartor O, et al. Three-year Safety of Radium-223 Dichloride in patients with Castration-resistant prostate cancer and symptomatic bone metastases from phase 3 randomized apharadin in symptomatic prostate cancer trial. Eur Urol 2017 [Epub ahead of print].