Thursday, February 18, 2021

Xofigo 2.0

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. 

The combination of Xtandi and Xofigo is being tried in the EORTC1333/PEACE 3 trial, which is still recruiting. Because of the problems with the ERA 223 trial, they sent out a safety alert to assure that everyone in both arms was also getting a bone-strengthening agent. Bertrand Tombal reported that skeletal events so far occurred in:
  • 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
It is too early to ascertain whether the combination increases radiographic progression-free survival.

Agarwal et al. reported on a small Phase 2 trial where 39 metastatic castration-resistant men were randomized to Xofigo+Xtandi or Xtandi alone. Bone metabolic markers were reduced significantly by the combination, suggesting increased efficacy. A safety analysis found few serious cytopenias and no skeletal events in either arm. A new post-hoc analysis found:
  • 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.
Presumably, the combination has a deleterious effect on the bone microenvironment or structural integrity. While Zometa has been proven to have no effect on survival as a monotherapy, in a subset of the STAMPEDE trial the combination of Zometa and Celebrex increased survival by 22%. Patients should not combine Xofigo with a second-line hormonal therapy without a bone-strengthening agent, and preferably only in a carefully watched clinical trial. Using them sequentially may be safer. Patients may wish to discuss adding Celebrex as well.

Clinical trials combining Xofigo with second-line hormonals include these:

Chemotherapy

Morris et al. reported the results of a small trial comparing Xofigo + docetaxel to docetaxel alone in 53 castration-resistant men who had ≥ 2 bone metastases. They were given either:
  • 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
With 52 weeks of follow-up:
  • 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
It seems that the more toxic docetaxel dose could be reduced by the combination without any loss of efficacy.

Xofigo was also found to work well after docetaxel. Docetaxel's effectiveness was not diminished by previous Xofigo.

These clinical trials combine docetaxel and Xofigo:
Immunotherapy

There is a synergy between radiation and immunotherapy (see this link). Radiation kills cancer cells and their proteins (antigens) are detected by immune cells that form antibodies to them. 

Marshall et al. reported the results of a small trial that randomized 32 mCRPC patients to Provenge + Xofigo or Provenge alone. After median follow-up of 5.3 months:
  • 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
Increases in PFS and reductions in PSA and bone ALP are usually not seen for either medication alone, so it is noteworthy that the combination had an enhanced effect.

But immune stimulation will never be long-lasting. Eventually, the immune system will regard the cancer cell as if it were a normal healthy cell of one's own and will stop attacking it. To continue the attack, a different sort of immune encouragement is required. These "checkpoint blockers" are currently represented by drugs that have been FDA-approved for use in other cancers, like Yervoy (ipilimumab) and Keytruda (PD 1 inhibitor).  This trial did not find any clinical benefit in combining Xofigo and Tecentriq. (atezolizumab). Hopefully, future Xofigo clinical trials will include a checkpoint blocker as well as an immune stimulant. There are two ongoing clinical trials at UCSF and in Melbourne of Lu-177-PSMA-617 combined with Keytruda.

This clinical trial includes an arm where patients receive Xofigo + external beam radiation + Bavencio (avelumab):
PARP inhibitors

PARP inhibitors (e.g., olaparib, rucaparib, etc.) have known activity in men who have certain DNA-repair defects, particularly BRCA mutations (either germline or somatic). They boost the deficiency in self-repair, causing the cancer cells to die. They may also be useful in conjunction with radiation. When radiation creates sublethal DNA damage, preventing the DNA-repair machinery from operating, a PARP inhibitor may put the cell over the edge.

van der Doolen et al. reported the results of an exploratory retrospective analysis of 93 castration-resistant patients at Johns Hopkins treated with Xofigo for bone metastases:
  • 28 had DNA-repair defects (DRD+)
  • 65 had no DNA-repair defects (DRD-)
Compared to the men who were DRD-, the DRD+ men had:
  • 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
Xofigo seems to work especially well in men who are DDR+. The combination of PARP inhibitors and Xofigo may be especially effective. There is a trial in Australia of a PARP inhibitor combined with Lu-177-PSMA-617.

These clinical trials examine the effect of DRD+ or PARP inhibitors on Xofigo effectiveness:
Earlier Treatment

A lab study at M.D. Anderson found that Xofigo was excellent at treating micro-metastases, but not as good at treating large bone metastases. This suggests that earlier Xofigo treatment may be preferable, and that larger tumors are optimally treated with a combination medical therapy or with a combination with external beam radiation (see below).

In a retrospective study, survival after Xofigo treatment was associated with better performance status, lower PSA at the time of treatment, lower pain scores, less use of advanced hormonals, lower bone scan index, and normal ALP levels.

Hematologic toxicity and bone marrow failure are potential adverse events associated with using Xofigo after extensive bone metastases are already present (see this link and this one). A clinical study showed that high tumor burden predicted skeletal-related events (SREs) and lower overall survival.

Xofigo has only been tested in men with bone-metastatic CRPC, who have bone pain and no visceral metastases. It's use in earlier states of progression have been unexplored.

This clinical trial includes Xofigo for biochemically recurrent patients before metastases are visible:
External Beam Radiation

Because Xofigo is especially good at targeting micrometastaic bone metastases, and not so good at targeting the macroscopic bone metastases, it may be optimal to target the visible ones (if there are very few) with SBRT, and the invisible ones with Xofigo.

These clinical trials include Xofigo as well as SBRT to oligometastases:
Radiosensitizers

There are several known radiosensitizers (medicines that increase the cell-killing potential of ionizing radiation). The problem with many radiosensitizers is that they may sensitize healthy cells too, increasing toxicity. Ideally, we want a medicine that only radiosensitizes cancer cells, while not affecting or even being radioprotective of healthy cells. Among the types of medicines being explored for this affect are PARP inhibitors and other DNA-damage repair inhibitors (above), heat shock protein inhibitors, HDAC inhibitors, idronoxil, and a plethora of natural products. Veyonda (idronoxil) has had some promising results when combined with Lu-177-PSMA-617 (see this link). So far, there are no clinical trials pairing radiosensitizers with Xofigo.

Retreatment

While there was no benefit found in increasing the dose per treatment over 55 KBq/kg or extending the number of consecutive treatments beyond 6 (see this link), repeat treatment may be beneficial. Sartor et al. found that repeat cycles are effective and well-tolerated. Multiple treatments are commonly used for Lu-177-PSMA-617.

 BAT

The RESTORE - Cohort C trial of bipolar androgen therapy (BAT) found that testosterone-loading among men who had not had Xtandi or Zytiga only had a benefit among men with lymph node-only metastases. This raises the possibility that Xofigo may be complementary to BAT in men with both lymph node and bone metastases.

This clinical trial will combine Xofigo and BAT in mCRPC patients:

Th-227 decays into Ra-223. While Th-227 readily chelates to the PSMA ligand, Ra-223 does not. So it is possible that as it decays, the Ra-223 detaches and may be picked up by bone tissue, just as Xofigo does. If so, there may be a double treatment effect.

This clinical trial uses Th-227-PSMA-antibody:
For those trying to decide between Lu-177-PSMA and Xofigo, here's a comparison (but not a randomized comparative trial) about the way the two radiopharmaceuticals work.

No comments:

Post a Comment