Combo Trials Aim to Clarify Optimal Radium-223 Use in mCRPC

Russell Szmulewitz, MD

While researchers are still determining how to optimally administer the radiopharmaceutical radium-223 dichloride (Xofigo) to patients with metastatic castration-resistant prostate cancer (mCRPC), there are ongoing studies exploring how the agent synergizes with chemotherapy and androgen-deprivation therapy (ADT).

For example, 1 randomized phase II trial is administering ADT with or without radium-223 in patients with newly diagnosed mCRPC with bone metastases (NCT02582749). In the study, which has not yet begun recruiting but is estimated to enroll 204 patients, radiological progression-free survival (PFS) will be the primary endpoint. Secondary endpoints include grade 3 to 5 treatment-related adverse events, time to first skeletal-related event, 2-year prostate-specific antigen (PSA) PFS and 2-year overall survival (OS). The estimated primary completion date is January 2018.

A second phase II study—1 using an immunotherapeutic approach—is testing sipuleucel-T (Provenge) in patients with asymptomatic or minimally symptomatic bone-metastatic CRPC (NCT02463799). The trial, which is currently recruiting patients, is aimed to determine whether the addition of radium-223 will increase the immune response and antitumor effect against the cancer.

Other studies are expected to study radium-223 in earlier treatment settings, explains Russell Szmulewitz, MD, associate director of the Genitourinary Oncology Program, assistant professor of Medicine, the University of Chicago Medicine.

OncLive: What is the optimal use of radium-223?

In an interview with OncLive, Szmulewitz discusses the unknown optimal use of radium-223, the appropriate time to administer it, and the associated challenges with the agent for the treatment of patients with mCRPC. He also sheds light on the ongoing clinical trials examining radium-223.Szmulewitz: That is a great question, and, honestly, we do not know. The largest study looked at patients who have castration-resistant prostate cancer and pain from their disease, who either had received chemotherapy and progressed, or were not eligible for chemotherapy. That is the place where we have the most data available.

When is the most appropriate time to administer radium-223?

What ongoing studies are looking at radium-223?

However, those patients are already some of the most frail and sickest patients, and perhaps the magnitude of benefit for the agent would be bigger if we used it earlier on in patients who have high-volume disease with bone metastases. In practice, we are using it before chemotherapy in patients who have bone disease only—and slight symptoms from their disease—and in whom maybe we think chemotherapy would be too harsh. There will be studies over the next 3 to 5 years that will help us place radium-223 perhaps earlier in the disease.The most appropriate time is when they have a high burden of bone metastases, but their bone marrow is still intact. They still have great blood counts. Perhaps [it is best to receive it] before their second-line chemotherapy—if they receive docetaxel early on, for example. After abiraterone acetate (Zytiga) or enzalutamide (Xtandi) is where I am using it the most and where I think it is probably the most appropriate.There are studies that are just getting underway in the castration-sensitive setting, in which patients who are getting either hormone therapy alone or hormone therapy with chemotherapy will also get radium-223 either after their chemotherapy, or in conjunction with their androgen-deprivation therapy in chemotherapy. That is going to take a few years to read out, but that is 1 possibility.

What are some of the biggest challenges with radium-223?

There are also smaller studies that are looking at combining it with sipuleucel-T immunotherapy in patients who have bone metastases. There are places where I think that we will see it move forward over the next few years.With that drug in particular, we still do not have a good readout for success. The PSA response rate, which is widely used, is historically around 10% with that agent. That being said, many patients benefit without having a PSA response. Therefore, 1 challenge is, how do we monitor it? Should patients get all 6 [doses]? Should patients get more than 6, although that is not the label? Some of the biggest challenges with the medication will come about in understanding who is benefiting during it, and who will benefit before it, in addition to not knowing exactly when to use it.