Xofigo (Radium 223 dichloride) is a systemic radiopharmaceutical. Radium is chemically similar to calcium and is taken up by bones in places where bone is actively growing, as in prostate cancer bone metastases. Radium 223 emits powerful alpha radiation that kills the cancer cells in the bone metastases. It has been found to double 2-year survival (see this link), extending survival time and reduce the skeletal-related events by almost a third. It often will not reduce PSA or show bone metastases shrinking in imaging, which some patients find disappointing.
It is FDA-approved for castration-resistant men with painful bone metastases, who do not show evidence of visceral metastases on a CT or MRI (lymph node metastases are allowed). So far, it is only FDA-approved as a monotherapy, but researchers have wondered whether it may be more effective in combination with other medicines, or used in other situations.
Always use with a bone-preserving agent
Hijab et al. reported the results of the REASSURE trial. They compared the bone fracture rate of 36 mCRPC patients who took Xofigo to a matched reference cohort of 36 mCRPC who didn't take Xofigo. They were all assessed for fracturesat baseline, 3 times during treatment and every 3 months thereafter with whole-body mpMRI. Very few (2-4 in each cohort) took a bone-strengthening agent. After 16 months of follow-up, they found:
- 56% had new fractures
- 3.7 fractures per patient with fractures
- 13.6 months to first new fracture
- ⅔ of new fractures were in the spine
- Only ⅓ were at sites of metastases
- Half the fractures were asymptomatic (no pain)
- No association of Xofigo dose with risk of fracture
- Higher # of bone metastases, high ALP, and previous use of steroids were associated with higher risk of fractures.
In the reference cohort (mostly using Zytiga or Xtandi, no Xofigo), there was still an increased fracture rate, albeit lower. After 24 months of follow-up, they found:
- 33% had new fractures
- 1.3 fractures per patient with fractures
- Only 38% occurred at sites of metastases
This trial shows that all men taking hormone therapy for mCRPC are at high risk for fracture, but particularly if they use Xofigo, and if they previously used corticosteroids (e.g., with chemotherapy). The effect on bone continues after Xofigo is stopped. These are predominantly "fragility" fractures, not metastasis-related, and can be prevented with bone-strengthening agents like Xgeva or Zometa.
Second-line hormonal therapies
It has long been known that androgen deprivation therapy (ADT) sensitizes prostate cancer cells to radiation therapy. Could a more powerful type of hormonal therapy work even better?
The combination of Zytiga and Xofigo was tried in the ERA 223 trial. The trial was stopped early because there were about 3 times more fractures in the group receiving the combination than in the group receiving a placebo and Zytiga. The combination now carries a black-box warning against the combined use.It appears that the problem may be at least partly resolved by using a bone-strengthening agent (like Xgeva or Zometa). When they looked at the subgroup who had taken bone-strengthening agents, 15% of those taking Xofigo+Zytiga vs 7% of those taking Zytiga-only experienced a fracture. So, even though Zometa or Xgeva reduced the fracture rates by about half in both arms, the fracture rate was still twice as high among those taking the combination.
- 33% of men taking Xofigo and Xtandi without a bone-strengthening agent
- 3% of men taking Xofigo and Xtandi with a bone-strengthening agent
- 13% of men taking Xtandi and a bone-strengthening agent
- PSA progression-free survival was 9 months for Xofigo+Xtandi vs 3 months for Xtand-alone (not significantly different on this small sample size)
- Time to PSA progression after the next therapy was 19 months for Xofigo+Xtandi vs 8 months for Xtandi-alone (significantly different)
- Time to next therapy was 16 months for Xofigo+Xtandi vs 3 months .for Xtandi-alone (not significantly different)
- Overall Survival was 31 months for Xofigo+Xtandi vs 21 months for Xtandi-alone (not significantly different)
- There were 3 asymptomatic fractures found in the Xofigo+Xtandi arm.
- Xofigo (55 KBq/kg) every 6 weeks for 5 injections and lower dose docetaxel (60 mg/m2) every 3 weeks for 10 infusions
- Standard dose docetaxel (75 mg/m2) every 3 weeks for up to 10 infusions
- The normal schedule for Xofigo is 55 KBq/kg once every 4 weeks for 6 injections
- The normal schedule for docetaxel is 75 mg/m2 once every 3 weeks for 6 infusions
- The timing adjustments were made for patient convenience
- Almost all had tried a second-line hormonal therapy
- Most were taking a bone-strengthening agent
- Median PSA progression occurred after 6.6 months in the combination arm vs 4.8 months in the docetaxel-only arm
- PSA declined by ≥ 50% in 61% of the combination arm vs 54% of the docetaxel-only arm
- Median radiographic or clinical progression occurred after 12 months for the combination vs 9 months for docetaxel only
- All 10 treatments were given for the combination, whereas there was a median of 9 of 10 treatments in the docetaxel-only arm
- 12% discontinued treatment in the combination arm vs 23% in the docetaxel-only arm
- Serious adverse events were suffered by 48% in the combination arm vs 62% in the docetaxel arm
- Serious blood disorders were noted more often for docetaxel-only
- Median progression-free survival (PFS) was 10.7 months for the combination vs 3.1 months for Provenge alone.
- The % who had a PSA reduction by more than half was 33% for the combination vs 0% for Provenge alone
- The % who had an alkaline phosphatase reduction of more than 30% was 60% for the combination vs 7% for Provenge alone
- There were no increases in side effects for the combination
- 28 had DNA-repair defects (DRD+)
- 65 had no DNA-repair defects (DRD-)
- Twice as high alkaline phosphatase (ALP) response: 80% vs 39%
- Longer time to ALP progression: 6.9 mos vs 5.8 mos. (not statistically significant)
- Longer time to next systemic therapy: 8.9 mos. vs 7.3 mos. (not statistically significant)
- Twice as long overall survival: 36.3 mos. vs 17.0 mos.
- Better Xofigo completion rates: 79% vs 47%
- No difference in PSA response