Sequential and Combined Therapies in mCRPC

There is not currently a definitive answer on how to best combine and sequence androgen receptor (AR)-directed therapies and radium-223 for patients with metastatic prostate cancer, since results from clinical trials assessing the combination are not yet available. There is an ongoing phase II study looking at radiographic endpoints of enzalutamide plus radium-223 versus abiraterone/prednisone plus radium-223 versus radium-223 alone. In addition, a larger randomized registration trial is assessing abiraterone plus radium-223 versus radium-223 alone.

For now, these combinations are being utilized off-label, says Daniel P. Petrylak, MD. In a patient with predominant lymphadenopathy (eg, >3 cm), it’s very tempting to add an AR-targeted agent, comments Celestia Higano, MD, FACS. The long-term impact of these combinations is still unknown, particularly regarding optimal timing and long-term impacts, like acquired resistance mutations or changes in the androgen receptor, notes Raoul S. Concepcion, MD, FACS.

Other combination strategies are looking at immunotherapy with radium-223. In the case of sipuleucel-T, prolonged immune activation has been seen, even 6 to 7 years after treatment, says Petrylak. In melanoma and other solid tumors, radiotherapy is associated with the Abscopal effect, which renders the cells more immunogenic. The question of whether this is true of radium-223 is currently being studied. To explore these agents together, a randomized phase II study is assessing sipuleucel-T with or without radium-223 in men with asymptomatic/minimally symptomatic bone-metastatic castrate-resistant prostate cancer.

AR-directed therapies are also being considered for combination studies with sipuleucel-T. Research has suggested that low-dose prednisone, which is co-administered with abiraterone, does not affect the immune system. As a result, both abiraterone and enzalutamide are candidates for combination approaches. Separate clinical trials have shown that concurrent administration of abiraterone or enzalutamide did not impact the ability to successfully manufacture and administer sipuleucel-T.

Another commonly asked combination question concerns whether to continue denosumab along with radium-223. Denosumab was not yet available for men with prostate cancer during the initial trial of radium-223 (ALSYMPCA), notes Higano. However, a subanalysis of the study did demonstrate a benefit for patients who received both radium-223 and zoledronic acid, which is another bone-targeted agent that is intended to prevent skeletal-related events.

Based on this subanalysis, both Concepcion and Higano recommend the continuation of bone-targeted therapy, either denosumab or zoledronic acid, when giving radium-223. There is an opportunity with this combination that is often overlooked, emphasizes Higano. In many instances, education regarding bone-targeted therapy is lacking for men with metastatic prostate cancer, adds Concepcion.