Sequencing Strategies for Radium-223: Still in Its Nascence?

Neal Shore, MD

Neal Shore, MD, of Atlantic Urology Clinics, a 21st Century Oncology affiliate, was named president-elect of the Large Urology Group Practice Association (LUGPA). He recently visited the OncLive News Network studios to discuss his role in LUGPA and provide his clinical insights about skeletal complications and the sequencing of radium-223.

“I am honored to be appointed to this prestigious position within LUGPA and look forward to furthering the organization’s goal [of] ensuring that quality urological care is available for all patients,” said Shore in a statement.

An internationally recognized expert in systemic therapies for patients with advanced urologic cancers, Shore serves as the National Urology Research Director for 21st Century Oncology. In this role, he has taught continuing medical education courses with the American Urological Association (AUA), serving as co-director for five courses through the association’s office of education.

OncLive: Congratulations on your status as president-elect. Can you explain your new responsibilities?

Dr Shore: Quite frankly, it’s to do whatever I can to help the entire executive board, under the leadership of our president, Gary M. Kirsh, MD. I will be offering guidance to the planning committee, the secretary of the annual meeting, and the CME presentation program, to name a few. I’m working on the bylaws committee and the benchmarking committee.

I’m particularly proud of the work LUGPA has conducted in active surveillance (AS). Our data on AS will be presented by Jeremy Shelton, MD, and it involves 1200 patients within 8 LUGPA practices. Detractors of community-based healthcare, suggest that urologists may be predisposed to interventional therapies for all newly diagnosed prostate cancer patients whereas our AS rates have well exceeded 30% for low-risk patients, which were presented at this year’s AUA in New Orleans.

An emphasis of LUGPA includes its advocacy activities that take place at the federal and state levels. Many legislative interests would like to curtail the ability of physicians to practice independently, and regulate the ownership of certain facilities, such as surgery centers, diagnostic radiology services, in-house laboratories, or the partnering with radiation oncologists. We have responded by demonstrating our contemporaneous data, which demonstrates our clinical efficacy for patient care. We have ongoing initiatives at both the clinician level and the advanced practice provider level to continue to enhance patient reported outcomes.

We’re working with the American Urological Association and the Society of Urologic Oncology to expand LUGPA’s educational activities and patient benefits. And we’re working to assist our colleagues in understanding the transition from volume to value, bundled payments, risk sharing, shared decision making and the plethora of new payment models that will ensue over the next few years.

A study¹ involving olaparib presented during this year’s American Association of Cancer Research (AACR) annual meeting demonstrated a good response in a molecular subgroup with metastatic castrate-resistant prostate cancer (mCRPC). What kind of implications does this have?

Some of the best work on poly ADP ribose polymerase inhibitors has been conducted by Karen Knudsen, PhD. It’s exciting to see that we might have another distinct mechanism of action and a therapy that can help patients with advanced prostate cancer.

Olaparib came about from its use in gynecologic malignancy, so I’m glad we can cross-pollinate and bring the findings over to advanced prostate cancer. The first time we had a new treatment for mCRPC was docetaxel in 2004, and since 2010 we’ve had six new therapeutics.

The problem is that we don’t have all the sequencing ironed out yet. We need to further understand downstream pathways, mutational phenomenon, backdoor pathways, and more so that we can at some time point conceivably cure advanced prostate cancer.

Skeletal event complications must be kept in mind when treating prostate cancer patients. What role does radium-223 (Xofigo) play?

The development of denosumab (Xgeva) and zoledronic acid (Zometa) is important in delaying skeletal related event complications. Neither of those two drugs has been shown to improve survival or delay mortality. But they are both beneficial and are part of all international guidelines for consideration for prevention of complications of bone metastases in mCRPC patients.

Abiraterone acetate (Zytiga) and enzalutamide (Xtandi) have demonstrated a decrease in skeletal related events. We also see a delay in symptomatic skeletal events with radium-223. More importantly, radium-223 not only demonstrated a statistically significant delay in SSEs, but this is the first bone-targeted agent that actually improves survival. Other radiopharmaceuticals have never demonstrated a survival benefit.

In the ALSYMPCA phase III study, the median overall survival (OS) for patients with bone metastatic castration resistant prostate cancer was about 3.6 months. About 55% of patients had received chemotherapy and 45% had not. For the group that did not receive chemotherapy, median survival was 4.6 months. The postchemotherapy group had a median survival of 3.1 months.

The take-home message is the importance of identifying patients as early as possible to get the benefit of the therapy. The approval of radium 223 is an important advance in the castration-resistant prostate cancer space, and it gives us another therapeutic option that prolongs patient survival and is very well tolerated.

How do you sequence or combine other therapies with radium-223?

Radium 223 has s a unique mechanism of action amongst the CRPC therapies. The radium particle goes to the bone metastases sites where there is hydroxyapatite mineralization. Its mode of action is not specifically directed toward the androgen receptor, nor toward the mitotic spindle as chemotherapeutic agents. It’s really working where there is mineralization and hydroxyapatite formation. This has intriguing combinatorial strategies as you can have different agents with different mechanisms of action potentially synergizing both for short term as well as long term disease impact.

Certainly, we look forward to additional peer reviewed data.

I presented data at the recent American Urological Association meeting from an expanded-access study that demonstrated that concomitant treatment with abiraterone acetate or enzalutamide did not alter the well-established safety profiles of all 3 therapies, and that there may be an early signal of an enhanced survival benefit .²

Regarding sequencing, we continue to investigate optimal strategies. We can assess the AUA, ASCO, and NCCN guidelines for guidance but must still have an understanding of the trial literature in conjunction with individualizing to patient co-morbidities and preferences.

References

1. Mateo J, Sandhu S, Miranda S, et al. Phase II trial of the PARP inhibitor olaparib in sporadic and unselected metastatic castration resistant prostate cancer (mCRPC). Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract CT322.
2. Shore ND, Vogelzang NJ, Fernandez D, et al. Radium-223 dichloride in expanded-access setting in the United States: overall and concurrent experience with abiraterone or enzalutamide. Presented at: American Urological Association Annual Meeting; Tuesday, May 19, 2015; New Orleans, LA. Abstract MP87-12.