Prostate cancer phenotype facilitates both imaging and therapy. Specifically, prostate cancer bone metastatic sites are thicker and disorganized, and therefore detectable with 99mTc MDP studies. Delivery of a radioactive load to metastatic sites is possible with molecular radiotherapy. Both alpha and beta emitters exist, but differing molecular profiles affects their therapeutics. Since alpha emitters are large in size, they can only travel short distances within tissue and require less hits to kill the target cell. Multiple randomized control trials exist examining single agent beta emitting radionucleotides however in summary: the studies are small, have pain response rates of ~40-60%, there is dose limiting toxicity and no survival benefit has been demonstrated. Radium 223 is a targeted alpha therapy that attacks both osteoclasts and osteoblasts.
The phase 3 ALSYMPCA trial published in the New England Journal of Medicine randomized patients with metastatic castrate resistant prostate cancer to radium 223 + best standard of care compared to placebo + best standard of care. Primary and secondary outcomes included overall survival and time to first skeletal related event, amongst others. The median overall survival was 14.9 months for radium-223 compared to 11.3 months for placebo (HR 0.70, 95%CI 0.58-0.83, p<0.001). Additionally, time to first skeletal related event was 15.6 months for radium-223 compared to 9.8 months for placebo (HR 0.66, 95%CI 0.52-0.83, p<0.001). Radium-223 also had an acceptable toxicity profile compared to placebo.
To improve the therapeutic ratio of Radium-223, future studies need to be performed investigating an increased number of cycles or therapeutic dose. Additional inquiries into combination therapy with Abiraterone, Enzalutamide, Docetaxel or Immunotherapies are potential options. Hypothesis generating data from an international, single arm phase 3b trial showed improved survival for co-treatment with Abiraterone or Enzalutamide and with Denosumab.
The ERA-223 trials compared Abiraterone + steroids + Xofigo to Abiraterone + steroids + Placebo. Data is currently being analyzed, however the timing of Abiraterone may be important in its concomitant use with Radium-223.
Finally, in metastatic hormone naïve prostate cancer patients, the ADRRAD trial is a Phase 1/2 evaluating T1-4N0-1M1b patients treated with Docetaxel x 6 cycles with ADT followed by 74 Gy XRT to the prostate and nodes with Radium 223. Toxicity and quality of life are primary endpoints with secondary endpoints focusing on WBMRI response, PSA/ALP, and CTCs. Initial response seems intriguing.
In summary, the bone remains the most significant metastatic cite in castrate resistant prostate cancer. Radium-223 has an overall survival benefit with low toxicity profile. Questions remain regarding bone targeted treatment with molecular radiotherapy including the value/safety of combination therapy, the timing of treatment in castrate resistant prostate cancer, response assessment, and to better understand the interaction between Radium-223 and the bone microenvironment.
Presented by: Joe M. O’Sullivan, MD, FRCR, Queen's University Belfast
Written by: David B. Cahn, DO, MBS @dbcahn, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA