Radium-223 Focus of Several Ongoing Combination Studies in mCRPC

A. Oliver Sartor, MD

A randomized study is underway to determine if the combination of sipuleucel-T (Provenge) and radium-223 (Xofigo) may improve outcomes in patients with metastatic castration-resistant prostate cancer (CRPC), according to a poster at the 2015 ASCO Annual Meeting presented by Jong Chul Park, MD, and colleagues.¹

Park, from the Johns Hopkins University School of Medicine, and colleagues hypothesized that combining radium-223 and sipuleucel-T would enhance the immune response produced by sipuleucel-T, due to increased antigens produced by radiopharmaceuticals. Since a majority of patients with metastatic CRPC have bone metastases, the researchers felt this approach could be implemented in patients who are asymptomatic or minimally symptomatic to achieve the greatest clinical benefit.

The randomized study will compare the antigen-specific immune responses seen with sipuleucel-T alone versus the combination of sipuleucel-T and radium-223 in patients with CRPC with bone metastases and no visceral involvement. The investigators reported that this is the first trial to examine the interaction between an alpha-particle (radium-223) and an immune-based therapeutic agent.¹

In the study, patients are being randomized to receive 3 infusions of sipuleucel-T plus 6 infusions of radium-223 (Arm 1) or 3 infusions of sipuleucel-T alone (Arm 2). The primary endpoint will assess whether the addition of radium-223 to sipuleucel-T enhances immune response. This will be measured by peripheral PA2024-specific T-cell proliferation 6 weeks after the first sipuleucel-T infusion. Clinical endpoints include incidence and severity of adverse events and laboratory abnormalities, median time to prostate-specific antigen progression, median time to radiographic progression, and median time to occurrence of first skeletal-related event. The investigators note that the enrollment of 15 men per study arm will yield an 80% power to find a 3.6-fold increase in proliferation response between the arms.¹

A total of 4 centers are expected to participate in the trial, with Johns Hopkins and Tulane Cancer Center as the leading study sites. Enrollment will begin in September 2015 with a projected accrual rate of 3 patients per month for 12 months. The study will last approximately 2 years.¹

This study joins a number of other investigations that are looking to move novel therapies for men with prostate cancer forward in the treatment paradigm. Following an explosion of new therapies, each with novel mechanisms of action, the goal for clinical trials now is to discover which agents operate well in combination.

In addition to radium-223 with sipuleucel-T, the radiopharmaceutical is also being assessed in combination with abiraterone acetate (Zytiga) for men with bone metastatic CRPC prior to treatment with chemotherapy. This ongoing phase III study will randomize patients in a 1:1 ratio to radium-223 plus abiraterone/prednisone or placebo with abiraterone/prednisone (NCT02043678).

The study will be conducted at nearly 150 sites and will enroll approximately 800 patients. The primary endpoint of the study is symptomatic skeletal event-free survival, with secondary outcomes focused on overall survival (OS), progression-free survival, and a number of other items.

"We ought not to be thinking about radium in the last line, we should be moving it up in the treatment sequence," one of the investigators on both radium-223 studies, A. Oliver Sartor, MD, medical director of the Tulane Cancer Center, said in an interview with OncLive. "We can combine radium with abiraterone and enzalutamide. We do know that those who received radium with abiraterone or enzalutamide do have a very favorable prognosis."

Aside from skin cancer, prostate cancer is the most frequently diagnosed cancer in men. It is estimated that 220,800 new cases will be diagnosed in the US during 2015.2 Prostate cancer is the second-highest cause of cancer death in men; an estimated 27,540 deaths are expected in 2015.²

Although early prostate cancer typically has no symptoms, late-stage cancer usually metastasizes to the bones. Most patients are diagnosed at an early stage, and active surveillance is frequently the best strategy. Patients with more advanced disease may be managed with hormonal therapy, chemotherapy, radiation therapy, or other treatments.² The survival of patients with metastatic prostate cancer progressing on androgen-deprivation therapy (ADT) has improved substantially over the past few years with the arrival of new therapeutic targets and options.³

Sipuleucel-T is an FDA-approved immunotherapy that has demonstrated an improvement in OS for men with asymptomatic or minimally symptomatic metastatic CRPC.⁴ Recent studies have shown that the antigen-specific immune response produced by sipuleucel-T is associated with improved survival, suggesting that a stronger immune response may result in even better clinical outcomes.^5,6

Radium-223 is a first-in-class alpha-emitting radiopharmaceutical approved for treatment of patients with CRPC and bone metastases. The agent selectively targets the area with increased bone turnover, delivering cytotoxic radiation with minimal myelosuppression.^7,8 Through a variety of mechanisms, including enhanced display of tumor-associated antigens, radium-223 may enhance immune modulation. The phase III ALSYMPCA trial demonstrated improved OS in patients with metastatic CRPC with bone metastases in the absence of visceral metastases and of lymphadenopathy greater than 3 cm; in addition, it provided bone-related palliation.⁹

References

1. Park JC, A. Sartor O, Sullivan R, et al. Randomized phase-2 study of sipuleucel-T with or without radium-223 in men with asymptomatic/minimally symptomatic bone-metastatic castrate-resistant prostate cancer (CRPC). J Clin Oncol. 33, 2015 (suppl; abstr TPS5076).
2. Cancer Facts and Figures 2015. Available at: http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed June 24, 2015.
3. Attard G, Parker C, Eeles RA, et al. Prostate cancer. Lancet. 2015 Jun 11. pii: S0140-6736(14)61947-4.
4. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
5. Sheikh NA, Petrylak D, Kantoff PW, et al. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castrate-resistant prostate cancer. Cancer Immunol Immunother. 2013; 62(1):137-147.
6. GuhaThakurta D, Sheikh NA, Fan LQ, et al. Humoral immune response against non-targeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome. Clin Cancer Res. 2015 Feb 3. pii: clincanres.2334.2014. [Epub ahead of print].
7. El-Amm J, Aragon-Ching JB. Radium-223 for the treatment of castration-resistant prostate cancer. Onco Targets Ther. 2015;8:1103-1109.
8. Henriksen G, Breistøl K, Bruland ØS, Fodstad Ø, Larsen RH. Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer Res. 2002;62(11):3120-3125.
9. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.