Biomarkers Show Efficacy of Radium-223/Docetaxel Combo in mCRPC

Michael J. Morris, MD

Radium-223 (Xofigo) plus docetaxel had a greater decline in tALP and in the bone formation markers, bALP and P1NP, than docetaxel alone in patients with bone-metastatic castration-resistant prostate cancer (mCRPC), according to results from a phase I/IIa clinical trial presented at the 2017 Genitourinary (GU) Cancers Symposium.

Fifty-three patients with mCRPC were randomized 2:1 to radium-223 with docetaxel versus docetaxel alone. P1NP, bALP, tALP, and prostate-specific antigen (PSA) were analyzed at 19 weeks and again 3 weeks after treatment.

By week 19, both arms saw an average decline in tALP, bALP, P1NP, and PSA of more than 30% from baseline. The median declines were greater in the radium-223 plus docetaxel arm versus the docetaxel arm alone, both at week 19 weeks and at the end of treatment.

In an interview with OncLive at the GU Symposium, lead study author Michael J. Morris, MD, an associate professor of Medicine at Memorial Sloan Kettering Cancer, discussed the significance of the phase I/IIa data.

OncLive: Can you give an overview of the effects of radium-223 with docetaxel versus docetaxel alone on bone biomarkers in patients with bone-metastatic CRPC?

Morris: We've spent some time developing a combination regimen of chemotherapy plus radium-223, with an intent to not just treat the boney compartment of metastatic prostate cancer but the tumor compartment as well. At this meeting we're presenting the biomarker data in terms of alterations in bone metabolism with the combination versus with chemotherapy alone.

How are these biomarkers identified and how do you use them?

Bone biomarkers for radium-223 assume particular importance because they're probably the most closely associated test that you can measure with a blood draw that is associated with survival. Radium-223 as a drug alone doesn't particularly impact PSA as other agents do. However, changes in bone biomarkers, such as alkaline phosphatase or bone alkaline phosphatase, do change significantly with radium-223. Those changes seem to be associated with improvements in survival.

These biomarkers were identified in the early stage clinical trials and the development of radium-223 and then they were used in the context of ALSYMPCA, the registration trial of radium-223. We've built them into this trial, which combines radium-223 with chemotherapy in order to see if they were similarly impacted.

The difference is that these patients are getting chemotherapy, so their PSA’s would be altered as well. We're looking at alterations both in PSA, which would be a tumor related biomarker with a bone biomarker and presumably the radium-223’s effects could be interpreted.

How do these results affect the use of radium-223 moving forward?

These biomarkers are going to be incorporated into the phase III trials of the combination of docetaxel and radium-223. I wouldn't say they impact clinical management at this point, but we are looking for biomarkers that can be prospectively followed by the clinician and used to interpret whether a patient is favorably responding to treatment or not.

It's important to look at this in terms of PSA versus these bone biomarkers because with the combination we don't know which will be most significantly impacted and if it is impacted, which would be most significantly associated with survival.

Since we were looking at both bone biomarkers of resorption and deposition, we saw that the bone biomarkers of deposition were more significantly impacted than those of resorption. That makes sense because radium-223 is deposited at the osteoblastic interface of the bone. We'll have to wait for the phase III trial to know whether that is associated with the clinical benefit or not.

Is the phase III trial ongoing?

There are going to be 2 phase III trials, both are right now in the protocol development phase. One is going to be run through the NCI cooperative group system, which is going to be for metastatic castration-sensitive prostate cancer. The current design for that trial is hormonal therapy and docetaxel as the control arm and hormonal therapy, docetaxel, and radium in the investigational arm with the primary endpoint being overall survival.

The second phase III trial is for castration-resistant metastatic disease, which includes the same 2 arms and it is essentially a study that mirrors what we just presented, which is docetaxel versus docetaxel plus radium-223.

What do you hope that community oncologists are going to take away from your presentation?

I think all doctors who take care of metastatic prostate cancer want to know if patients are benefitting from treatments or not. That is singularly difficult to do with radium-223 because the usual habituated look at PSA does not really apply to radium-223. In my opinion, it is encouraging to see that this regimen, even in combination with chemotherapy, does seem to recapitulate the importance of bone biomarkers to see if they are responding or not.

It would be too early to say that the changes in the bone biomarkers reflect that patients are living longer and doing better. We're not there yet, but given the previous data from ALSYMPCA showing their association with survival, it is encouraging to see that the same message essentially carries through to this regimen in combination with chemotherapy and that it wasn't only seen with radium-223 alone. We'll see how closely associated it is with survival in the phase III trials and that is the point where we could say to the community physicians that this is something that you can use to assess response to this regimen.

Morris MJ, Loriot Y, Fizazi K, et al. Effects of radium-223 (Ra-223) with docetaxel versus docetaxel alone on bone biomarkers in patients with bone-metastatic castration-resistant prostate cancer (CRPC): a phase I/IIa clinical trial. Presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abstract 154.