First Approved Alpha Emitter Bolsters Arsenal Against Prostate Cancer

Oliver Sartor, MD

With the recent approval of a first-in-class radioactive isotope as a treatment for prostate cancer, urologists have a new weapon in their rapidly growing arsenal of therapies designed to fight this disease.

The intravenously administered treatment, radium-223 dichloride (Xofigo), is generating excitement among urologists and oncologists, and not just because it is the first alpha-emitting radiopharmaceutical ever approved by the FDA for use in humans. During the phase III ALSYMPCA trial that led to its May 15 approval, the drug prolonged survival and increased time to bone progression in patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known metastatic disease.

Now, practitioners will need to explore how the drug is going to best fit into their practices.

According to Oliver Sartor, MD, medical director, Tulane Cancer Center, and professor of Cancer Research in the Departments of Medicine and Urology at Tulane University School of Medicine in New Orleans, Louisiana, an important basic guideline is that radium-223 is not a replacement for older therapies for prostate cancer, but instead complements many existing treatments extremely well. While Sartor, who helped design and run the ALSYMPCA trial, doesn’t recommend using the drug with other radiopharmaceuticals, or with chemotherapy until more research is conducted, he noted that the field beyond that is fairly open.

“I don’t use radium-223 in and of itself—I am always using it with another therapy, typically hormonal therapies,” said Sartor, who was the trial’s North American principal investigator. “In keeping with the design of the trial, patients can get best supportive care, manipulate their hormones, or take bisphosphonates if they want while radium is administered. So the nice thing about this drug is that it works well with other treatments. Today, many of these patients are managed with new hormone therapies like abiraterone and enzalutamide, and administering those in combination with radium, quite frankly, is a smart thing to do.”

Furthermore, oncologists who had early access to radium-223 during and after the trial agree that the drug is easy to administer and boasts a good safety profile.

Mechanism of Action

Nicholas J. Vogelzang, MD, a medical oncologist at Comprehensive Cancer Centers of Nevada (CCCN) and a clinical researcher at US Oncology in Texas, was a bit startled when he heard data in 2007 about radium-223 in prostate cancer.

“I saw the first report of the drug being effective and was intrigued, because who would have thought that a radium associated with atom bombs and radioactive fallout would be useful for treating cancer?” recalled Vogelzang, who participated in the ALSYMPCA trial in its final months, when CCCN joined as an expanded access site. “When I was growing up, we had to hide under our tables for atom bomb testing, and one of the things we were told to do was to take a shower if we were exposed to nuclear fallout. A shower washes off the alpha particles, which are in the dust and will burn the skin.”

When it’s directed toward an appropriate target within the body, though, radium-223 has proven quite safe, Vogelzang said.

While gamma particles penetrate tissue the most deeply and beta particles have a more limited penetration, alpha particles— which are the largest—are the most superficial in their reach, Vogelzang explained. At the same time, they’re powerful, he said, meaning they can pack a punch without hitting far beyond their target.

“It’s really very safe, but when it does hit something it’s like a bowling ball hitting a piece of glass: The glass shatters,” Vogelzang said. “The DNA is damaged very easily by these big alpha particles. You can give it in the vein, and it doesn’t burn the vein. Even if you inject it under the skin it doesn’t really burn the skin very much, but it localizes to where bones are being made. That’s important, because where bones are being made is where the cancer sits.”

Consisting of two protons and two neutrons, an alpha particle is able to kill cancer in and around bone because it is a calcium mimetic, going where calcium does—preferentially targeting sites of osteoblastic metastasis where there’s a lot of bone turnover, rather than normal bone or marrow, Sartor explained.

“In the osteoblastic metastases, you have a lot of osteoblastic activity laying down an organic matrix and then an inorganic matrix,” he said. “The organic matrix is filled with hydroxyapatite, and the radium binds to the hydroxyapatite. It’s very nice because the radium doesn’t actually bind with the tumor, but with the regions around the tumor. These areas are exactly where it needs to radiate, and it does so very well.”

An injected radiopharmaceutical like radium-223 differs from external-beam radiation and brachytherapy because it’s “liquid radiation that homes to the bone spots,” Vogelzang said.

It is less likely than external-beam radiation to damange normal tissue and, unlike brachytherapy, radium-223 does not have to be surgically placed; rather, it can be given intravenously in any vein, Sartor said.

The drug, which has a physical half-life of just over 11 days, “prolongs survival in patients with advanced bonemetastatic CRPC unlike any other form of radiation,” he added.

Previously approved radiopharmaceuticals for the treatment of prostate cancer—samarium 153 (Quadramet) and strontium 89 (Metastron), both beta emitters—ease pain, but don’t prolong survival, Sartor explained.

“I used strontium 89 many years ago, and it was very effective, but you couldn’t give it more than once or twice,” Vogelzang recalled. “Then came samarium, which is still on the market. I still use it from time to time because it’s very effective in controlling pain. I remember a schoolteacher who was in a lot of pain, didn’t want to quit school, and didn’t want to take chemotherapy. I gave him that drug, and he was able to go back to school the next week.

Nicholas J. Vogelzang, MD

“Those drugs work, and the approval of radium-223 builds upon that—without the burden of side effects that those other drugs gave us,” Vogelzang said.

Sartor added that radium-223 has an advantage at the molecular level.

at a single-cell level from the bloodstream,” Sartor said. “The interesting finding is that, from the same patient, one cancer cell and the next cancer cell are not necessarily the same; heterogeneity extends down to the cellular level. One of the reasons I like radium is that it has the ability to overcome some of the problems with genetic heterogeneity. The alpha particle really doesn’t care what type of mutation you have; it will pretty much kill them all.”

Early Approval

Radium-223 was approved 3 months prior to the mid-August decision date originally anticipated by the FDA.

Neal D. Shore, MD, who treated patients with radium-223 as part of an early-access program, posited that the early approval was based on the strength of the data supporting the drug’s usefulness.

“I’m not part of the FDA panel, but I think it’s always really great to see the FDA moving with alacrity for a very unique and novel therapeutic that’s going to help our patients with advanced prostate cancer,” said Shore, medical director of Atlantic Urology Clinics in South Carolina and its independent clinical research arm, the Carolina Urologic Research Center. Those organizations partnered with the Coastal Carolina Radiation Center, in North Carolina, to offer the fledgling drug, and after its approval, Shore was the first physician worldwide to administer the radiopharmaceutical to a patient.

“The FDA saw not only its clear efficacy in terms of improvement in survival and delay in skeletal complications for patients with bone metastases in the CRPC population, but it also saw that it’s very well tolerated,” Shore said of radium-223. “It’s remarkable in that we didn’t see any of the significant myelosuppression that we’re familiar with when giving the beta and gamma particles. In addition, this radioisotope is cleared through the intestinal tract, so it’s excreted fecally and we saw very, very low levels, or mild events, of diarrhea.”

The double-blind, randomized, mutinational ALSYMPCA trial compared radium-223 against placebo and best standard care in patients with CRPC and at least two bone metastases. According to updated results presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO),¹ patients in the radium-223 arm of the study experienced a median overall survival of 14.9 months compared with 11.3 months in the placebo arm (hazard ratio [HR] = 0.695; 95% CI, 0.581-0.832; P = .00007). In the radium-223 arm, the time to the first skeletal-related event was a median of 15.6 months, a significant improvement over the 9.8 months in the placebo arm (HR = 0.658; 95% CI, 0.522-0.830; P = .00037).

According to the FDA, the most common side effects reported during clinical trials were nausea, diarrhea, vomiting, and swelling of the leg, ankle, or foot. The most common abnormalities detected in blood tests included anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia.

“This 900-plus patient trial showed that patients who got the radium lived longer than those who did not get the radium,” Vogelzang said. “They had reduced pain. They had reduced blood cancer markers, and they needed less opium or morphine. Their side-effect profile actually reduced, because in a majority of the patients, what we describe as side effects come not from medication, but from the cancer itself. They needed fewer x-rays, and they didn’t break their bones as often.”

Those benefits led to delays in the need for additional treatment, Shore said, including “a delay in the onset of a radiation requirement for painful bone metastases and other delays in skeletal events, such as surgical intervention and core compression.”

“This is the ideal drug that the FDA should approve,” Vogelzang said, “and they did.”

Who Is Eligible?

About 70% of men with advanced metastatic CRPC will be eligible for radium-223 at some point in their lives, Sartor said. Although patients need to be symptomatic to receive the drug, he noted, symptoms don’t have to be severe.

“Symptoms don’t mean you are taking morphine opiates all the time,” he said. “Symptoms can mean that you are taking something like acetaminophen or even another steroidal, aspirin, Advil, ibuprofen, or something like that. It turns out that you don’t have to be very symptomatic in order to benefit, because this is a drug that prolongs survival. Yes, it does relieve pain, but it prolongs survival.”

The drug was particularly effective in study participants with a fairly early stage of prostate cancer that had spread to bone—even if they were older, Vogelzang said.

“The trial allowed men who didn’t want chemotherapy, or who were not fit for chemotherapy,” he said. “We know that many of these men are very old and not healthy and are not good candidates to be treated with chemotherapy, but in fact they had more benefit than the men who had previous chemotherapy.”

Patients on the other end of the symptom spectrum, however, may end up frustrated if they’re hoping to take radium-223, Vogelzang said. The drug doesn’t work at all in tumors outside bone, he pointed out.

New Analyses Support Drug’s Benefits

Sartor and colleagues presented a post-hoc analysis of pain parameters in ALSYMPCA at the 2013 ASCO annual meeting, confirming that treatment with radium-223 reduced pain and opioid use in CRPC patients with bone metastasis.²

Neal D. Shore, MD

“The pain analysis is a verified questionnaire, a validated composite of four questions that assess pain,” Sartor said. “In this context, there were two findings: (1) that use of radium-223 would decrease the amount of pain, and (2) very importantly, that it would have an opiate-sparing effect. That means that people who receive the radium are less likely to require opioid analgesics. I think it is a very important message, particularly in our elderly patient population.”

In another analysis, Sartor and coauthors considered bonealkaline phosphatase (ALP) as a prognostic factor for the success or failure of radium-223 in patients with metastatic CRPC.³ They concluded that higher baseline levels of total ALP were associated with an increased risk of death, and pointed out that because patients on the ALSYMPCA trial experienced a decline in ALP, further analysis is warranted to determine whether there is a correlation between total ALP dynamics and survival.

In another study presented at ASCO this year, Vogelzang and colleagues analyzed whether prior docetaxel use had any impact on the effectiveness or safety of radium-223 in the study’s population.⁴ The authors found that, while the use of the radiopharmaceutical significantly prolonged overall survival and was safe in patients regardless of prior docetaxel use, those who had used the chemotherapy faced a slightly increased rate of grade 3/4 bone marrow suppression when using radium-223.

In another analysis,⁵ Vogelzang and coauthors found that, while the use of radium-223 and docetaxel were the strongest prognostic factors for decreases in neutrophils and platelets in the study’s population, participants still faced a low risk for hematologic adverse events.

Radium-223 in the Community Setting

So how will radium-223 fit into community practice? The drug is easy to administer, given intravenously over the course of 45 to 60 seconds once every 4 weeks for a total of six doses, Shore said.

“From the patient’s perspective, you walk in, you get it, and you go,” Vogelzang said. “You don’t have to worry about nausea, vomiting, or hair loss. It’s a really easy drug for older patients. They literally can drive into our office, get weighed, get their blood count checked, get the drug in their vein, and say ‘See you next month.’”

However, the new drug must be administered by someone with the appropriate licensure—typically, a radiation oncologist or nuclear medicine radiologist.

“I think the practical and clinical applications for administering this therapy are not going to be daunting whatsoever,” Shore said. “Initially, people might see it as an obstacle and hurdle that the drug needs to be administered by someone licensed to handle radiopharmaceuticals. However, some of the larger urology and medical oncology groups are integrated, or they’re multidisciplinary, so they have radiation oncologists built into their practice. Where that’s not the case, I think there are many urologists and medical oncologists who have great affiliations with their hospital-based nuclear medicine radiologists.”

A more provocative question, Shore suggested, is how practitioners should combine, or sequence, radium-223 with other drugs.

“The fun question is, ‘How can I give this, or can I give this, with some of the other newly approved therapies that have come along since 2010 that help our patients with CRPC, such as sipuleucel-T, abiraterone, enzalutamide, docetaxel, and cabazitaxel?’” Shore said. “In the ALSYMPCA trial, patients were just stratified to have received or not received docetaxel or zoledronic acid, because when that study was done, these other therapies weren’t available. So, I think it will be important to have investigator-initiated trials, and perhaps cooperative group studies or industry-sponsored studies, to give us a greater comfort level. It doesn’t strike me that there should be a challenge, intuitively, in giving these other therapeutics concomitantly, but we have to get the data, we have to do the studies, and that’s very important.”

Until there are guidelines, physicians should use their judgment to make case-by-case decisions about combinations and sequencing involving radium-223, and also be sure to give the new drug strictly according to its label, Shore said.

Looking ahead, Sartor noted, there may be other uses for radium-223 in cancer treatment.

“There is a series of trials for radium-223 being conducted in breast cancer (NCT01070485),” he said. “Plus, there is a lot of discussion about trials at this point in multiple myeloma. There certainly needs to be more work done, and there are no phase III trials, so that is an area of interest that is going to take more planning.”

References

1. Parker C, Nilsson S, Heinrich D, et al. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer patients with bone metastases (ALSYMPCA). J Clin Oncol. 2012; 30 (suppl; abstr LBA4512).
2. Nilsson S, Sartor AO, Bruland OS, Fang F, Aksnes A-K, Parker C. Pain analyses from the phase 3 randomized ALSYMPCA study with radium-223 dichloride in castration-resistant prostate cancer patients with bone metastases. J Clin Oncol. 2013; 31 (suppl; abstr 5038).
3. Sartor AO, Amariglio R, Wilhelm S, et al. Correlation between baseline variables and survival in the radium-223 dichloride phase III ALSYMPCA trial with attention to total ALP changes. J Clin Oncol. 2013; 31 (suppl; abstr 5080).
4. Vogelzang NJ, Helle SI, Johannessen DC, et al. Efficacy and safety of radium-223 dichloride in castration-resistant prostate cancer patients with bone metastases who did or did not receive prior docetaxel in the phase 3 ALSYMPCA trial. J Clin Oncol. 2013;31(suppl; abstr 5068).
5. Parker C, Garcia-Vargas JE, O’Bryan-Tear CG, Fang F, Vogelzang NJ. Hematologic safety of Ra-223 dichloride in castration-resistant prostate cancer patients with bone metastases from the phase 3 ALSYMPCA trial. J Clin Oncol. 2013;31(suppl; abstr 5060).