Neal D. Shore, MD
Radium-223 dichloride (Xofigo) is a unique agent that differs dramatically from other earlier radiopharmaceuticals and other approved agents used in castration-resistant prostate cancer with bone metastasis (mCRPC), says Neal Shore, MD, medical director of Carolina Urologic Research Center.
Earlier radiopharmaceuticals, such as strontium-89 (Metastron) and samarium-153 (Quadramet), were used mainly for palliative pain and did not improve survival.
Radium-223, which demonstrated a median overall survival (OS) of 14 months versus 11.2 months with placebo (HR, 0.70; P = .00185) in patients with mCRPC in the ALSYMPCA trial, has a very different mechanism of action than other agents used to treat the disease, says Shore. It targets the bone metastases directly and greatly improves survival outcomes, he says.
“A bone metastasis is a very powerful biologic prognostic indicator. It is a seminal event in the progression of prostate cancer,” says Shore. “It can indicate a worsening prognosis and a decrease in the patient’s survival probability.”
In an interview with OncLive, Shore discusses the evolution of radiopharmaceuticals, how radium-223 works, and its potential for use in combination with other agents.
OncLive: How has the field of radiopharmaceuticals evolved in recent years?
Shore: Earlier generations of radiopharmaceuticals were used for patients who were suffering from widespread bone metastatic disease that was not amenable to pharmacologic therapy, follicular radiation, or approved chemotherapy. For the most part, it was used as a “last ditch option” to help patients who were usually in very significant pain.
These were radiopharmaceuticals that were available as end-of-life care. Neither of the approved therapies—strontium-89 or samarium-153—ever demonstrated a survival benefit in any stage III trial. They were used for pain palliation, and with their use there was a very high rate—typically north of 25%—of significant myelosuppressive effects. These included neutropenia and thrombocytopenia.
With the approval of radium-223 in May 2013, this changed our treatment options. The ALSYMPCA trial, which was a double-blind randomized controlled trial, included men with mCRPC with bone metastatic disease who had some form of symptomatology related to bone disease—primarily pain.
These men were on some sort of analgesic for their pain. Approximately 55% were on a narcotic analgesic and about 45% were not. Moreover, about 55% had received prior chemotherapy and about 45% had not. The trial demonstrated, for the first time ever, a radiopharmaceutical extending OS.
The median OS in the entirety of the trial was 3.6 months. When we did a post hoc analysis, we found that, in patients who had not received chemotherapy, there was a 4.6-month median OS. In the patients who had received chemotherapy, who presumably were even more progressed regarding their tumor burden, there was a 3.1-month median OS.
What is the mechanism of action of radium-223, and how does it compare with other agents?
The take-home point is that this is a drug that is a survival prolonging agent, much like the novel hormonal lines of therapy abiraterone acetate (Zytiga) or enzalutamide (Xtandi). It is also a survival-prolonging agent as much as the immunotherapeutic sipuleucel-T (Provenge) and the two taxane-based chemotherapies docetaxel and cabazitaxel (Jevtana).
Radium-223’s mechanism of action is entirely different from all of the other approved mCRPC therapies because it works as a calcium mimic. In other words, the radium partical is attracted to hydroxyapatite minimization sites where there is bone metastasis. The mechanism of action is to enhance double-stranded DNA breaks, resulting in difficultly for repair mechanisms to ensue, and an enhanced ability to create apoptosis and cell death.
The particle radium-223, in distinction to prior radiopharmaceuticals, is a much physically larger particle so it has a shallow penetration and works at the cortical bone region where the metastatic tumor deposits are described on typical imaging technology. It has less penetration in the marrow. Therefore, what we have seen in the ALSYMPCA trial and subsequent trials, papers and posters, is that the incidence of myeloproliferative suppression of bone marrow tissue is very, very low.
What agents do you see potential for use in combination with radium-223?
At the 2016 Genitourinary Cancers Symposium, we presented an interim analysis of an investigator-initiated sponsored study. There were 5 investigational sites, including my own, where we enrolled 32 patients who received on-label indication, concomitant use of abiraterone acetate with prednisone in conjunction with radium-223.
We looked at all safety and tolerability for any infusion but, ultimately, we will report on the quality-of-life measures and pain measures, as well as safety and tolerability in all patients receiving the full course of radium-223. There were monthly questionnaires given on quality of life, fatigue, and pain, as well as CT scan after the third course of radium-223.