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Radium-223, Looking for a Dance Partner

Radium-223 is actually quite capable of dancing on its own without a partner.  It offers an overall survival, symptomatic skeletal events and multiple pain and quality of life benefits for patients with bone metastatic castration-resistant prostate cancer and symptoms.1  Yet, the ALSYMPCA trial, which established the beneficial effects of radium-223, did not mandate regular imaging, so image surveillance expectations are uncertain.  Additionally, prostate-specific antigen (PSA) level does not always associate with clinical outcomes with Radium-223.  Given the mechanism of action of Radium-223, as an alpha-particle emitting radiopharmaceutical that incorporates into areas of osteoblastic activity, it is not surprising that alkaline phosphatase serves as not only a good baseline prognostic marker2 but also a good treatment response biomarker.3

However, a practical challenge is that radium-223 is often thought of as a pain palliative agent, similar to strontium-89 and samarium-153.  It is often administered to patients very late in the disease course in heavily pre-treated patients.  On the contrary, the ALSYMPCA trial actually had >40% of men who were not even on narcotic pain medications, and almost half the men on trial had not received docetaxel.  Additionally, there are stringent requirements for absolute neutrophil count, hemoglobin and platelet count for treatment.  Waiting late in the disease course leads to higher likelihood of inability to administer the compound due to myelosuppresion either from previous chemotherapy or marrow involvement of prostate cancer.  The development of visceral disease also may happen later in the disease course and would exclude a patient from radium-223.  Hence, strategies for increasing permeation of radium-223 are to combine the agent with therapeutic partners that make biologic sense, that may decrease the PSA level to alleviate patient and physician stress and that introduce the agent earlier in the disease course.

From post-hoc and expanded access programs, hypothesis generation has been formed that patients receiving radium-223 with either abiraterone acetate or enzalutamide, seems to have better outcomes than with radium-223 alone.4  Additionally, there is data to show that combination with skeletal-related events prevention agents like denosumab or bisphosphonates, may also offer benefits over radium-223 alone.4  This may be due to the potential for these agents to effect osteoclastic activity while radium-223 has osteoblastic activity.

As a result, there are many ongoing prospective clinical trials evaluating various combination treatments with radium-223.  For instance, the ERA 223 trial is evaluating abiraterone with radium-223 vs. abiraterone with placebo.  The trial is fully accrued and we await results on the primary endpoint of symptomatic skeletal event free survival.  The PEACE-3 trial is enzalutamide with radium-223 vs. enzalutamide alone with the primary endpoint of radiographic progression free survival by Prostate Cancer Working Group 2 criteria.5  PEACE-3 is actively accruing.  Both of the above trials distinguish themselves in that neither requires symptoms for eligibility.  Other approaches are combining radium-223 with immunotherapy agents such as sipuleucel-T, pembrolizumab or atezolizumab.  With all the excitement surrounding DNA repair deficiency in prostate cancer,6,7 there is even a trial now combining a PARP inhibitor, niraparib, with radium-223.

These trials all offer strong rationale for our consideration of patient accrual.  They introduce radium-223 at earlier time points when the disease may not yet be exhibiting clinical symptoms.  They also combine with androgen pathway inhibitors, immunotherapy agents and DNA repair agents, all very exciting agents for prostate cancer patients.  Since radium-223 induces double strand breaks, it is ideal for combination with PARP inhibitors, especially in a biomarker enriched setting.  Additionally, since radium-223 induces potent cell kill, it may release neoantigens into the blood stream, allowing for immunotherapy agents to have increased opportunity for success.  Hence, although radium-223 offers clear benefit to our patients with metastatic castration-resistant prostate cancer and symptoms, we now have the opportunity to enhance efficacy with the below clinical trials.

Written by: Evan Yu, MD

Combination clinical trials with Radium-223:

Radium-223 Dichloride and Abiraterone Acetate Compared to Placebo and Abiraterone Acetate for Men With Cancer of the Prostate When Medical or Surgical Castration Does Not Work and When the Cancer Has Spread to the Bone, Has Not Been Treated With Chemotherapy and is Causing no or Only Mild Symptoms (ERA 223)

A Randomized Multicenter Phase III Trial Comparing Enzalutamide vs. a Combination of Ra223 and Enzalutamide in Asymptomatic or Mildly Symptomatic Castration Resistant Prostate Cancer Patients Metastatic to Bone.

A Phase 2 Study of Sipuleucel-T With or Without Radium-223 in Men With Asymptomatic or Minimally Symptomatic Bone-Metastatic Castrate-Resistant Prostate Cancer

A Randomized, Phase II Study Evaluating the Addition of Pembrolizumab (MK-3475) to Radium-223 in Metastatic Castration Resistant Prostate Cancer (mCRPC)

A Phase Ib, Open-Label Study of the Safety and Tolerability of Atezolizumab in Combination With Radium-223 Dichloride in Patients With Castrate-Resistant Prostate Cancer Who Have Progressed Following Treatment With an Androgen Pathway Inhibitor

Phase IB Trial of Radium-223 and Niraparib in Patients With Castrate Resistant Prostate Cancer (NiraRad)


References
  1. Parker C et al.  N Engl J Med 2013; 369:213-23.
  2. Sartor AO et al.  Ann Oncol 2017; 28:1090-7.
  3. Heinrich D et al.  ESMO 2016 Conference; Abstract 751P.
  4. Saad F et al.  Lancet Oncol 2016; 17:1306-16.
  5. Scher HI et al.  J Clin Oncol 2008; 26:1148-59.
  6. Robinson D et al.  Cell 2015; 161:1215-28.
  7. Pritchard CC et al.  N Engl J Med 2016; 375:443-53.