Looking Ahead: Xofigo's Role in Metastatic Prostate Cancer

Xofigo (radium-223 dichloride), a radiopharmaceutical, is an efficacious bone-targeted agent for patients with metastatic castration-resistant prostate cancer (mCRPC), though its optimal role for this group of patients is still evolving, according to Michael J. Morris, M.D.

For instance, the safety and efficacy of Xofigo is being explored alone or in combination with Xtandi (enzalutamide) or Zytiga (abiraterone acetate) in patients with mCRPC in a phase 2a study (NCT02034552). The primary endpoint of the open-label randomized trial is patient bone scan response.

Is Xofigo a major focus in the discussion about mCRPC treatment?

In an interview, Morris, an associate professor of Medicine at Memorial Sloan Kettering Cancer, shared his expertise on Xofigo’s current role in patients with mCRPC and how he anticipates that role will evolve going forward.A significant component is Xofigo. That is the only FDA-approved therapy in terms of a radiopharmaceutical that is bone directed with an alpha emitter. I’m hoping, within the next couple of years, we will see some tumor-directed radiopharmaceuticals—some of which are alpha emitters and some of which are beta emitters.

What have you found that sets Xofigo apart from other therapies?

Ultimately, we want to be able to target multiple compartments. The bone compartment and the tumor compartment are not necessarily the same. There are advantages to how you might be able to integrate directed therapy at the cancer, as well as the primary metastatic component that it occupies.It’s a first-in-class agent, so that sets it apart as it’s a stand-alone drug with really nothing else like it. This really gives it a level of interest that is unique.

Secondly, its mechanism of action lends a very low toxicity profile, unlike chemotherapy or other radiopharmaceuticals. It really does have very little in the way of hematologic toxicity. It prolongs life and delays skeletal-related events, so it has a huge opportunity to be combined with other agents.

It’s being combined right now in clinical trials with androgen receptor (AR)—directed agents. We have some early studies that are going to move into phase 3 of combinations with chemotherapy, and whether or not it could be combined with tumor-directed radiotherapy is an interesting question that we have yet to determine.

What is the logic behind the thinking that Xofigo/chemotherapy or Xofigo/AR-directed agents would have efficacy?

It’s uniquely suited for many patients with prostate cancer because it prolongs life with a minimum of side effects and it can overlap with other drugs. Right now, you can’t combine it with chemotherapy by its label, but we do have safety data on that. We are advancing to phase III and, hopefully in a few years, we will be able to coordinate these two therapies and demonstrate a survival prolongation. If you think of Xofigo as a bone-targeted agent, it is very effective at delivering a high degree of energy in a very narrow actual physical, penetrative distance in the bone. There is tumor that’s located deeper within the bone that presumably is outside the direct reach of an alpha particle. That doesn’t mean there can’t be indirect effects that impact a tumor that’s deeper within the bone. However, there is also a circulating tumor cell (CTC) component that’s not bone based, even in patients with bone-only disease by scans.

Then, there are patients who have nodal or visceral disease for whom Xofigo can’t reach. If you have a soft tissue component that’s visualized or not visualized but is present, and if you have tumor within the bone that is beyond the reach of an alpha particle, then it does make sense to apply some tumor-directed therapy. This is in addition to the bone-directed therapy to reach those compartments of disease that otherwise would be beyond the penetrative distance of an alpha particle.

Will Xofigo, or other next-generation radiopharmaceuticals, always have a role in the disease?

AR-directed therapy could help with visceral disease, a CTC component, or the boney disease that isn’t otherwise going to be hit by the alpha particle—in addition to the compartment contamination that the bone-seeking radiopharmaceutical provides.Part of that is philosophical. Tumor-directed therapy can be very effective but, if you think of it in environmental terms, one of the challenges of it is that it’s the equivalent of trying to kill a billion mosquitos. You can try to do that or you can try to drain the swamp. Bone-directed therapy has the latter approach and tumor-directed therapy has the former approach.

One approach will probably never be perfect, and it’s some blend of those of changing the whole environment plus targeting any residual disease that will ultimately render you to a tumor burden of both. That’s what our hope would be. Will 1 therapy be able to do that to the exclusivity of another? I doubt it. You are going to need a multi-pronged approach.