Radium-223 combined with Lupron demonstrated a median 3.6 month extension of overall survival, compared to the placebo (14.9 v 11.3 months). This was the outcome of a 928 man randomized trial (ASYMPCA) in asymptomatic or mildly symptomatic men with castrate-resistant prostate cancer metastatic to bone. Significant pain reduction was achieved with radium-223. The study required > 2 bone metastases and small volume pelvic or retroperitoneal lymph node enlargement was allowed. Radium-223 significantly delayed the progression of bone metastases by 6 months and, compared to placebo, showed a 30% decrease in death at the 2-yr mark.

What is the mechanism of action of radium-223:

Radium-233 naturally self-targets and selectively binds to the areas of increased bone formation (i.e. the function of osteoblasts) in a manner similar to calcium. As the isotope undergoes radioactive decay, it emits a high speed alpha particle (essentially a helium nucleus) from its position on the surface of the osteoblast. The particle penetrates cancer cells (and all other cells in close proximity) causing lethal double-stranded breaks. No cell cycling is required to establish vulnerability, as is necessary with chemotherapy.

The effective range of the alpha particle is 2 – 10 cell diameters accounting for its low level of bone marrow suppression, i.e., the production of platelets and white and red blood cells. The agent is safely administered intravenously in the clinic setting over a short interval and is dosed monthly for 6 cycles. Based on the ASYMPCA trial results radium-223 was FDA approved in 2013.

The clinical significance of osseous metastases:

Metastases to bone are a major cause of morbidity and mortality in men with metastatic CRPC. About 90% of men with CRPC will exhibit cancer spread to bone at some time in their disease course. Prostate cancer cells have a special affinity for the bone marrow space as a result of co-signaling between marrow elements (termed ‘stroma”) and circulating malignant prostate cells. One well substantiated theory envisions prostate cancer cells expressing small extracellular vesicles (‘exosomes’) containing RNA and DNA messages that home to the marrow and prepare a receptive microenvironment, a ‘metastatic niche’, into which the malignant cells are welcomed. A complex interaction develops — a ’vicious cycle’, wherein the osteoblasts stimulate cancer proliferation and vice versa. The resulting excessive bone formation and remodeling weakens the bone structure, predisposes to fracture, causes pain, and, when extensive, impairs the production of blood forming elements.

Studies combining radium-223 with other agents:

Combination therapy with radium-223 and either abiraterone or enzalutamide (with continuing Lupron) has been studied in the hope that the differing mechanisms of action of a hormonal agent and radium-223 would increase overall survival. However the large randomized trial (ERA-223) combining Lupron and radium-223 was halted early because of increase in fractures and death in the combo arm. In this trial the medium overall survival, however, in the two arms was not significantly different.

A companion trial in Europe studying the combo enzalutamide and radium-223 v placebo showed a similar increase in fractures. In a UroToday video “Decreased Fracture Rate When Adding Bone Protecting Agents to Radium-223: PEACE III”: https://www.urotoday.com/video-lectures/mcrpc-treatment/video/1331-embedded-media2019-06-08-23-22-13.html

[Control+click link to follow or copy and paste into browser]

Bertrand Tombal analyzed the PEACE trial and reported that ”If these patients are pre-exposed to bone-protecting agents (eg., Zometa or Xgeva) and bone-protecting agents are maintained, we haven’t seen any fracture in the first twelve months.”

How to evaluate response to radium-223 therapy: An informative article on this subject is: “Alkaline phosphatase in metastatic castration-resistant prostate cancer: reassessment of an old biomarker.” Theresa Guise, Future Oncology, 2018

Response evaluation should focus on changes in the serum level of the enzyme alkaline phosphatase.

Alkaline phosphatase is produced in the liver and in osteoblasts, the bone forming elements in the marrow. A more specific test, but more expensive and less commonly performed, is the ‘bone specific’ alkaline phosphatase (bALP) which is proportional to the enzyme production from osteoblasts. bALP constitutes 40 – 50% of the total alkaline phosphatase. However, the total serum ALP can serve as a proxy for osteoblast activity.

An intriguing biologic transformation has been discovered, termed ‘osteomimicry’, in which crosstalk between marrow osteoblasts and cancer cells awakens genes in malignant prostate cells to promote expression of ALP in the cancer cell contributing to the total serum level. This was determined by finding that circulating prostate cancer cells secrete ALP.

An increase in serum ALP is a hallmark of cancer activity in bone, and successful treatment with radium-223 leads to a rapid fall in the serum level. Conversely, an elevated “baseline ALP is prognostic for adverse overall survival and may be a better marker for overall survival than prostate-specific antigen in patients with bone-dominant mCRPS,” (ibid, Guise)

So where does radium-223 fit into the schema of treatment of metastatic CRPC?

The two currently commonest drugs used in this space, abiraterone (Zytiga) and enzalutamide
(Xtandi), each have been found in randomized trials to extend median overall survival ~ 4-5 months — essentially similar to radium-223. Since osseous metastases occur in 90% of men with mCRPC, either only in bone or in combination with spread to lymph nodes, these three agents share a similar target, although each acting with a different mechanism. This commonality of target is especially applicable to bone-only metastatic disease, making sequencing of the drugs a relevant issue.

This subject was covered in a lecture by Dr. Daniel George on April 4, 2019 presented by URO TODAY “Real World Treatment Experience with Radium-223” https://www.urotoday.com/video-lectures/crpc-w-bone-metastases/video/1298-embedded-media2019-05-03-14-45-40.html [Control+click link to follow or copy and paste into browser]
Dr. George is Professor of Medicine and Surgery, Duke University of Medicine and leads the Prostate and Urology Cancer Center. He draws on his clinical experience and his research on radium-223. He is a consultant with Bayer Pharmaceuticals the maker of Xofigo.

Take-away points from his lecture follow:

  • Early use of radium-223 in mCRPC is advised before the development of visceral metastases (wherein radium-223 is not FDA approved) and when hematologic function is good. A high ALP, indicative of extensive bone metastases, is prognostic for a poor response.

[Editorial comment: Other markers of unlikely response are an elevated LDH and a PSA doubling time of < 6 months. An excellent general reference on the use of radium-223 is “Current approaches to incorporation of radium-223 in clinical practice, Parker et al, Prostate Cancer and Prostatic Dis. Jan 2018]

  •  Optimal patients for radium-223 are those whose conditions are “stable enough to benefit from this agent,” and can sustain the 6 month period of treatment.
  • Dr. George takes issue with what he sees as the common practice of sequencing one hormonal agent following progression after the first hormonal therapy, noting that this practice produces only short responses, if any, and no significant survival benefit. Instead, after progression following the first agent, he would recommend choosing radium-223, which does yield a survival gain.

[Editorial comment: A comment from Parker (ibid): “Specifically, in patients who progress after receiving hormonal therapy, initiation of radium-223 or chemotherapy may be preferable to switching to another hormonal agent because of the limited efficacy resulting from cross-resistance.]

  • Dr. George prefers sequential use of radium-223 as opposed to concomitant with one of the hormonal agents.
  • Chemotherapy can safely be used before or after radium-223.
  • To avoid adverse skeletal events, it is best practice to combine radium-223 with a bone health agent such as a bisphosphonate, eg., Zometa or densumab, i.e. Xgeva.
  • Radium-223 is rarely associated with a PSA decline (3% in one study, 16% in another). This possibly is explained by radium-223 not targeting the androgen receptor as is also the case with Provenge. The PSA should not be used as a marker for response as successful treatment can occur despite a rising PSA. The marker to follow is the ALP.
  • Successful treatment is associated with an improved quality of life.

[Editorial comment: Not mentioned by Dr. George: Treatment with radium-223 can be repeated after a successful initial response if the blood counts are sufficient. (Sartor et al. J Clin Oncol, Feb 20, 2018). Before repeating radium-223 a CT scan is appropriate to ascertain that no visceral metastases have developed.]

BOTTOM LINE:
Radium-223 (“Xofigo’) offers yet another option in the continuing quest to prolong survival for men with metastatic prostate cancer while at the same time preserving quality of life.

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