Radium-223 Treatment Combinations Feasible For Metastatic Castration-Resistant Prostate Cancer

Research raises possibility of concurrent radium-223 and anti-androgen treatment for progressing metastatic castration-resistant prostate cancer

medwireNews: Phase IIIb trial results indicate that radium-223 may be used alongside abiraterone or enzalutamide for the treatment of bone-dominant, metastatic, castration-resistant prostate cancer, including asymptomatic patients.

The findings expand on the ALSYMPCA trial, conducted before the widespread use of the anti-androgens and denosumab, which demonstrated improved overall survival (OS) and skeletal benefits regardless of prior docetaxel use with the radiotherapeutic agent versus placebo in symptomatic patients unsuitable for docetaxel.

The joint primary endpoint of acute and long-term safety in the current study showed an “acceptable” profile similar to that reported for the earlier phase III trial, say Fred Saad, from Centre Hospitalier de l‘Université de Montréal in Quebec, Canada, and fellow Radium-223 International Early Access Program Investigators.

In all, 75% of 696 patients experienced at least one treatment-emergent adverse event, with grade 3 and 4 side effects in 11% and 1%, respectively. Radium-223 discontinuation due to adverse events occurred in 21%.

After a median follow-up of 7.5 months, the co-primary endpoint of median OS was 16 months and post hoc exploratory analyses indicated that OS was associated with baseline measures of alkaline phosphatase, haemoglobin, ECOG performance status and the presence of pain.

Of note, 17% of the 397 patients who were naive to abiraterone or enzalutamide at baseline began anti-androgen therapy concurrently with radium-223, 9% received sequential treatment, beginning anti-androgen therapy more than 30 days after their final radium-223 dose, and 74% did not receive either anti-androgen agent during the study period.

And post hoc exploratory analysis indicated that median OS was longer in patients who received concurrent abiraterone and/or enzalutamide than those who did not. Patients naive to these treatments at baseline who received endocrine therapy concurrently or sequentially with radium-223 also had longer OS than those who received only the radiotherapeutic agent.

Similarly, patients who received radium-223 concurrently with the RANKL inhibitor denosumab had longer OS than those who received radium-223 alone, whereas OS was comparable between patients given radium-223 with and without bisphosphonates.

“Data from these exploratory analyses are hypothesis-generating for future prospective studies to identify the optimal patient profile for radium-223 and for efficacious treatment combinations”, the researchers write in The Lancet Oncology.

Ravi Maden, from National Cancer Institute in Bethesda, Maryland, USA, and co-authors of an accompanying comment say the study provides “intriguing preliminary data” on how to overcome treatment resistance but agree that randomised trials are necessary to confirm efficacy.

“If radium-223 could extend the benefit of these anti-androgens beyond the emergence of resistant androgen receptor subclones, it could favourably impact disease progression and overall survival”, they write.

“Given the disparate mechanisms of action, combining radium-223 and anti-androgens seems to be a rational strategy to contend with androgen receptor-resistance”, the commentators say, adding that as preclinical findings suggest radium-223 may enhance immune response to cancer, the agent could have “additional relevance” as immune-based treatments emerge.

References

Saad F, Carles J, Gillessen S, et al. Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. Lancet Oncol 2016; Advance online publication 26 July. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30173-5 

Madan RA, Gulley JL, Dahut WL. Radium-223 in prostate cancer: emitting the right signals. Lancet Oncol 2016; Advance online publication 26 July. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30248-0

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