Moving Radium-223 Forward in the Treatment Timeline for Prostate Cancer With Bone Metastases

Richard G. Stock, MD

Radium-223 (Xofigo) has efficacy in treating patients with prostate cancer and bone metastases, but is usually introduced into the patient's traetment plan after they have symptomatic disease. These symptoms are often painful, and the metastases can be difficult to treat at this stage. Moving radium-223 up in the treatment paradigm for these patients could provide better outcomes and longer survival, according to Richard G. Stock, MD, professor and director of genitourinary oncology at the Icahn School of Medicine at Mount Sinai in New York.

“Clearly, what we know is, when bone metastases are present, patients have a decrease in overall survival. This is a problem that needs to be addressed, and skeletal tumor burden is an independent predictor of death in patients with advanced prostate cancer,” Stock said during a presentation at New York GU™: 11th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies.

Bone metastases are quite common in prostate cancer, Stock said. About 14% of the patients who undergo surgical or chemical castration will develop castration-resistant prostate cancer (CRPC), and about 90% of those patients will develop metastases in the bone. The 5-year survival rate for patients with bone metastases is about 30%.¹

Typically, prostate cancer progresses from nonmetastatic local disease (M0), with a possible rise in prostate-specific antigen levels and biochemical relapse, to CRPC when patients fail androgen-deprivation therapy. Patients with newly diagnosed metastatic CRPC (M1) are often chemotherapy naïve, and 4% of patients with prostate cancer present initially with M1, hormone-sensitive disease.

The treatment challenge is that prostate tumor cells may colonize the bone during this disease progression. In vitro data show that the colonization of bone tissue may be driven by chemoattraction and preferential attachment.^2,3 Prostate cancer metastases are also associated with osteoblastic activity, so the balance shifts from bone destruction to bone deposition, where the osteoblasts secrete more proteins to form excess bone beyond the body’s bone resorption capabilities. This leads to osteoblastic lesions in the mineralized bone tissue where tumor cells have gathered, and it correlates with higher levels of alkaline phosphatase and osteocalcin, which would signify liver or gallbladder toxicity.^4,5

When bone metastases are present, overall survival (OS) is lower. Results from a population-based cohort study of patients with prostate cancer showed that fewer patients with bone metastases were alive at 5 years (3%; 95% CI, 2.2%-3.4%) than patients with no bone metastases (56%; 95% CI, 54.9%-56.7%). In the study, 23,087 patients had an initial diagnosis of prostate cancer; 22,404 of those patients had no bone metastases, and 569 presented with bone metastases at diagnosis.⁶

Investigators in the field of prostate cancer therapeutics have seen different isotopes being used to treat bone metastases in patients with prostate cancer, but most have fallen by the wayside due to bone marrow toxicities. Radium-223 has remained a standard radiotherapy since its approval by the FDA in 2013, due in part to its more favorable toxicity profile and its mechanism of action.

Radium-223 is an alpha-pharmaceutical that targets bone metastases by mimicking calcium, forming complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The short range of the alpha particles emitted (<10 cell diameters) limits damage to the surrounding normal tissue, leading to less bone marrow toxicity. The alpha particles predominantly cause double-strand DNA breaks in adjacent cells, resulting in the antitumor effect on bone metastases.⁷

Because radium-223 is absorbed primarily by the bone marrow, there is a small risk for bone marrow—related toxicities, such as myelosuppression. However, radium-223 can also lead to adverse events (AEs) outside of the bone. The agent can be absorbed by other organs, including the gastrointestinal system, leading to AEs that can include nausea, diarrhea, and vomiting.⁷

Stock recommended watching out for these and other AEs. “For those of us who do this in a clinical practice, we check the blood count, and it is very rare that patients have to discontinue treatment due to myelosuppression,” he said. It is important, he continued, to monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Radium-223 should be discontinued in patients who experience life-threatening complications despite supportive care for bone marrow failure.

Stock also said that a key reason why radium-223 is an effective drug for patients with prostate cancer is how it’s eliminated. After an intravenous injection, less than 1% of radium-223 dichloride remains in the blood after 24 hours. Fecal excretion, the major route of elimination, removes 63% of the agent within 1 week; less than 5% is excreted through the urine.⁷

Table. Ongoing Clinical Trials of Radium-223 in Combination With Other Agents for Patients With CRPC and Bone Metastases

In the phase III ALSYMPCA study of radium-223 in patients with symptomatic CRPC with skeletal metastases (NCT00699751), results showed that radium-223 significantly improved OS versus a placebo (median OS, 14.9 vs 11.3 months; HR, 0.70; 95% CI, 0.55-0.88; P <.001). In a subgroup analysis of the study, radium-223 provided benefit to patients in all subgroups.8In a phase II prospective study of radium-223 in patients with CRPC with bone metastases (NCT01516762), results showed that the agent was well tolerated with no new safety concerns observed. The study found that patients with more advanced disease were less likely to benefit from radium-223, and investigators recommended that clinicians consider baseline characteristics and therapy sequence for greatest clinical value.⁹

The phase II prospective study was part of an expanded access program that was approved in 2012, with the goal to monitor acute and long-term safety of radium-223 in patients with CRPC and symptomatic bone metastases. The drug was made available at qualified clinical sites to patients who could not participate in a controlled clinical trial.¹⁰

Ultimately, Stock said, radium-223 is generally used early in the management of castration-resistant disease if the patient exhibits symptomatic bone metastases with or without small-volume pelvic or retroperitoneal lymph node metastases, with no evidence of visceral metastases, and with good hematologic function.

Looking to the future, there are other clinical trials testing the efficacy and safety of radium-223 in patients with prostate cancer with bone metastases combined with other therapies (Table). However, Stock cautioned that in a phase III trial (NCT02043678), radium-223 was combined with abiraterone (Zytiga), which led to greater risk of fractures.¹¹ “We now know not to use that combination treatment, although we don’t really know why it leads to the increased risk of fracture,” he said.

References

1. Cancer stat facts: prostate cancer. Surveillance, Epidemiology, and End Results Program. National Cancer Institute website. seer.cancer.gov/statfacts/html/prost. html. Accessed May 3, 2018.
2. Tsingotjidou AS, Zotalis G, Jackson KR, et al. Development of an animal model for prostate cancer cell metastasis to adult human bone. Anticancer Res. 2001;21(2A):971-978.
3. Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002;62(6):1832-1837.
4. Jung K, Lein M, Stephan C, et al. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. Int J Cancer. 2004;111(5):783-791. doi: 10.1002/ijc.20314.
5. Yang J, Fizazi K, Peleg S, et al. Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway. Cancer Res. 2001;61(14):5652-5659.
6. Nørgaard M, Jensen AØ, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 2010;184(1):162-167. doi: 10.1016/j.juro.2010.03.034.
7. Xofigo [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2013. accessdata.fda.gov/drugsatfda_docs/label/2013/203971lbl.pdf. Accessed May 3, 2018.
8. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium- 223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213- 223. doi: 10.1056/NEJMoa1213755.
9. Sartor O, Vogelzang NJ, Sweeney C, et al; U.S. Expanded Access Program Investigators. Radium-223 safety, efficacy, and concurrent use with abiraterone or enzalutamide: first U.S. experience from an expanded access program. Oncologist. 2018;23(2):193-202. doi: 10.1634/theoncologist.2017-0413.
10. Bayer initiated expanded access program for investigational compound radium-223 chloride [press release]. Wayne, NJ: PRNewswire; February 2, 2012. prnewswire. com/news-releases/bayer-initiates-expanded-access-program-for-investigationalcompound- radium-223-chloride-138559894.html. Accessed June 6, 2018.
11. Important drug warning. Xofigo (radium Ra 223 dichloride): important safety information update regarding increased incidence of deaths and fractures in an investigational phase III clinical trial with Xofigo used in combination with abiraterone acetate and prednisolone/prednisone. Bayer HealthCare Pharmaceuticals Inc. hcp.xofigo-us.com/downloads/pdf/PP-600-US-3282%20Xofigo%20November%20 2017%20DHCP%20Letter%20-%20Digital%20Version.pdf. Published November 30, 2017. Accessed May 3, 2018.