Radium-223 linked to longer overall survival in patients with castration-resistant prostate cancer with bone metastases

June 3, 2015. Radium-223, brand name Xofigo (formerly Alpharadin), is an FDA approved intravenous injectable treatment for painful bone metastases in men with castration-resistant prostate cancer (CRPC). The drug Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. Radium-223 is taken by intravenous injection once a month (every four weeks) for up to six months. Radium-223 received priority review two years ago based on its ability to extend Overall Survival as shown in its Phase 3 trial.

This June 1 at the ASCO meeting in Chicago, Fred Saad MD FRCS from CHUM Centre Hospitalier Universitaire de Montreal, Canada reported on followup to the original Phase 3 trial. This latest study confirms and possibly strengthens improvement in Overall Survival and finds no new safety concerns. Designed as a Phase 3b international multicenter trial, this followup was part of an early access program (EAP). It enrolled prostate cancer patients with metastatic castrate-resistant prostate cancer (mCRPC) from a dozen countries in Europe plus Canada and Israel.

Unsurprisingly, the followup finds that Overall Survival is longer for healthier patients and also for patients who at the start are taking additional drugs to protect bone and attack the cancer.

In the original Phase 3 study, called ALSYMPCA, patients with symptomatic bone metastases received Radium-223 and best standard of care, versus best standard of care and placebo. Treatment with the combination resulted in significantly improved Overall Survival (see slide below) at a median of 14.9 vs 11.3 months and delayed time to first symptomatic skeletal event (e.g. bone pain, measurable bone tumor, or cancer-related fracture).

The multinational followup study, Saad explained, enrolled 839 patients from 113 sites and 14 countries. Of these, 696 patients were treated with one or more doses of Radium-223. Some 58% received all 6 injections. Median patient age was 72 years; 88% of patients were high performance status (able to pursue normal or close to normal daily activities).

Baseline characteristics of study subjects were similar to the ALSYMPCA trial, with the exception of pain at baseline and prior and concomitant treatment. Pain was reported as: no pain 21%, mild-moderate 52%, and severe in 27% respectively. Some 60% of patients had already received prior therapy with docetaxel (Taxotere). At the start of and during the trial patients were also taking a variety of recently-approved drugs for advanced prostate cancer: 22% were taking abiraterone (Zytiga); 20% denosumab (Xgeva); 18% bisphosphonates (e.g. Zometa) and 4% enzalutamide (Xtandi).

At 16 months, median Overall Survival was comparable with ALSYMPCA OS results. Saad described at ASCO how the study's other preplanned goals related to its final analysis. The researchers set out to measure time to first skeletal-related event (SRE), and changes in ALP/PSA blood test levels indicating disease progression. Final analysis focused on Overall Survival in subgroup populations based on:

• use of other medication at baseline (i.e., abiraterone, enzalutamide, docetaxel, denosumab, and bisphosphonates)
• baseline total ALP values (a blood test for assessing bone turnover)
• baseline ECOG PS i.e. measure of patient's illness-related "performance status" from Fully Active to Disabled
• baseline pain.

Patients in different countries and from differently treated local populations may bring different levels of factors such as performance status, prior use of other medical drugs, and so on. Some may have had less intensive treatment than available in the USA. Others may be taking more advanced drugs. Between a current trial and its precursors, more patients may have access to newly approved medical drugs. Such is the case with e.g. abiraterone (Zytiga) and enzalutamide (Xtandi), which were unavailable at the start of the US-based Phase 3 Radium-223 (Xofigo) trial.

In comparison with the U.S. trial, the new data are stronger, said co-investigator Joe O'Sullivan, MD, from Queens University, Belfast. "Survival and toxicity data are more robust by virtue of the numbers of patients. This study also shows that the good safety profile of the drug was maintained, thereby supporting the good safety profile that was shown in the randomized trial."

Overall Survival was slightly longer than in the ALSYMCA trial, possibly because patients were treated at a slightly earlier stage. Dr. O'Sullivan said. Still, a median survival of 16 months compared very favorably to the 14-month survival data in the ALSYMCA trial O'Sullivan pointed out. This international trial also produced some "hypothesis-generating" analyses, O'Sullivan said.

"It would appear -- and again this is hypothesis-generating because patients were not randomized," Dr. O'Sullivan said, "that patients receiving abiraterone or enzalutamide along with radium had better survivals. Whether that's a synergistic effect or not is very hard to tell. But there is something – a separation of the survival curves which certainly merits further study."

Some ongoing large, randomized trials are testing the hypothesis of combining abiraterone or enzalutamide with Radium-223. Based on the data so far (albeit unrandomized). O'Sullivan said, "there would appear that there would be some effect." See link to active trials below.

"To me," Sullivan said, "the most reassuring thing, as a clinician treating patients, is that the toxicity profile remains good, and acceptable. And in real-world patients, it looks like the survival is in the range of – or slightly better than – what was seen in the ALSYMCA trial, at a median of 16 months."

Serious adverse events (Grade 3/4) occurred in 38% of patients. Of these, 21% of patients (1 out of 5) discontinued Radium-223 due to adverse event. A grade 3 event is categorized as "Severe but not life-threatening; hospitalization required; limitation of patient's ability to care for him/herself." A Grade 4 event is categorized as "Life-threatening; urgent intervention required." To put these events in perspective we need to compare them with 1) adverse events in patients not receiving treatment 2) adverse events in the earlier trial where fewer patients were taking other advanced drugs like abiraterone. Beyond this, of course, oncologists must compare adverse events for the other drugs taken alone.

In the earlier trial, as reported in The New England Journal of Medicine, "The number of patients who had adverse events after they received the study drug was consistently lower in the radium-223 group than in the placebo group for all adverse events. . . . Overall, no clinically meaningful differences in the frequency of grade 3 or 4 adverse events were observed between the study groups." This lessening of adverse events went along with a higher percentage of patients experiencing "a meaningful improvement in the quality of life" (notably through pain reduction) and prolonged survival.

Dr. O' Sullivan, reviewing the new trial, agreed that the additional Overall Survival benefit could simply arise from the new hormonal agents (abiraterone or enzalutamide) which didn't exist or weren't widely available at the time of the ALSYMCA trial.

"It's interesting how the goal posts are shifting in the castrate-resistant prostate cancer patient," he said. "We're seeing better survivals, and I guess we're trying to figure out where all the new therapies fit in a sequence. These data, although they don't answer the question, at least help us think about this and help us to understand that it's reasonably safe to combine these agents, without encountering any significant additional toxicity."

For current or planned clinical trials using Radium-322 alone or with drugs such as abiraterone or enzalutamide see Clinical trials of radium ra 223 dichloride active as of June 3, 2015.

Reported by Jacqueline Strax from ASCO-15 session highlights and resources below.