Combinations Key to Advances With Bone-Targeting Agents in mCRPC

John C. Araujo, MD, PhD

Radium-223 dichloride (Xofigo) remains the sole radiopharmaceutical that benefits patients with metastatic castration-resistant prostate cancer (mCRPC) from both a skeletal-related event (SRE) and overall survival (OS) perspective.

However, questions, John C. Araujo, MD, PhD, what can the prostate cancer community do to improve these outcomes even further?

An ongoing phase Ib clinical trial is exploring the potential of the PD-L1 inhibitor atezolizumab (Tecentriq) in combination with radium-223 for patients with mCRPC whose disease has progressed on treatment with an androgen receptor (AR)-pathway inhibitor (NCT02814669).

In the study, investigators will determine the safety and efficacy of this regimen, for which they will test patients in a concurrent administration and then in a staggered format should patients be unable to tolerate the regimen concurrently. Forty-five patients are expected to enroll; the primary endpoints will be the percentage of patients with dose-limiting toxicities, percentage with adverse events, and percentage with objective responses.

OncLive: What were the key takeaways from your discussion on bone-targeting agents in mCRPC?

Araujo, an assistant professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed targeted therapies—current and emerging—for patients with bone-metastatic CRPC during the 2017 OncLive^® State of the Science Summit on Genitourinary Malignancies. In an interview, he went into further detail about these radiopharmaceuticals and what the field can accomplish with them over the next year.Araujo: The main points that will be made for the oncologists that I’d like them to take home will be, first, that the greatest morbidity and mortality from prostate cancer is from metastatic disease to the bone. The current agents available that do target bone decrease the number of SREs, which would mean fractures, increase in pain, and spinal cord compression. Two of the agents, zoledronic acid and denosumab, decrease the number of SREs, but do not increase OS in these patients.

We’ve known about radium-223 for some time now. Is there any new data on the treatment?

Is there any rationale to develop newer-generation radiopharmaceuticals?

Why is bone metastasis incidence so high in mCRPC? Is there something with the tumor biology?

If you were giving a talk on bone-targeted agents 1 year from now, what questions do you hope we will have answered by that time?

However, radium-223 did decrease the number of SREs and increase OS. These are the current FDA-approved agents in prostate cancer that target bone.There have been interesting combinations performed with chemotherapy, AR-antagonists, and AR-pathway blocking agents. Therefore, to see results with those combinations will be interesting in the future, as radium-223 solely targets bone—as far as we are aware. By combining these agents, one might be able to increase survival by targeting not only spread to bone, but also spread to other organs such as the liver and lungs.There are none that I am aware of. Currently, on the periodic table using that group of elements, I do not see any other agents being tested now at this time. There are a few older elements, including Strontium-89 and Samarium-153; however, they have fallen a little out of favor in prostate cancer with the approval of radium-223.That is something that we have been working on for some time. Clearly, everyone does realize that prostate cancer does have a proclivity to go to bone. That’s the most fundamental problem with the disease after it spreads. It is also the most costly in terms of money, as well as cost in life, due to prostate cancer. However, it’s unclear what is actually in the bone marrow that either attracts the disease or that prostate cancer likes to go there, to find something that it needs, to survive. No direct signal has been confirmed as of yet.Since we are seeing an increase in the number of liver hepatic metastases, I am hoping that over the next year we will determine whether combination therapies that target the bone, as well as possibly the AR, would be more beneficial in these patients and increase OS.

What message do you have for the community oncologists who attended your lecture tonight?

That would be the goal for the next year: newer agents that could kind of target both areas would also be of benefit.One aspect that I would like the clinical oncologists to realize is that, even in my practice, I actually do not know which agents to use first and in what order. We seem to believe that certain agents work better upfront—possibly docetaxel before radium-223. However, we really do not know. I don’t want them to go home with more questions, but they may go home with more questions regarding which agents to use first and the sequence of these agents.