I was confronted with a decision in the clinic this week about whether or not to use radium-223 for a patient with metastatic castration-resistant prostate cancer (mCRPC). He was on the older side, mid to late 80’s and his performance status was declining rapidly. He had persisted for quite some time with relatively low volume disease, in fact, just pelvic lymph nodes. As those progressed, he developed urinary outlet obstruction (even though the nodes weren’t that big) with multiple urinary tract infections (UTI) and, during a several month period marked by brief hospitalizations, relatively rapid failure of next-generation androgen receptor (AR) antagonists, all amidst the COVID-19 (SARS-CoV-2) pandemic, metastatic disease in the bone blossomed in multiple sites, and it was associated with relatively mild pain.
Sounds like exactly the type of patient for whom radium-223 was approved: Mostly bony disease, pain, not fit for chemotherapy. The problem is that he really isn’t that ideal patient, and radium probably won’t be much help for him – because he probably doesn’t have enough time left to finish the full course. It is another example of a situation where a patient ‘looks good on paper’ but likely won’t benefit in real life. It was another example of how our world of evidence-based medicine of trying to follow the United States Federal Drug Administration (FDA) labels and clinical trial criteria we are often unable to stay within those lines. When we publish clinical trials and give lectures based on them, we talk about the patients who were on the clinical trial, who fit the eligibility criteria. The implication of those talks and papers is that we will be treating pretty much those exact patients in the real-world scenario. In the real world, however, we all know that a large population of patients exists out there who don’t fit within the lines of the clinical trial. They still need the opportunity to benefit from these treatments.
Radium presents us with a classic ‘window of opportunity” dilemma. Let’s take a look at why so many men miss windows of opportunity, in particular with radium, and what can be done about it.
- The benefit is likely more likely when more doses are given. This is an obvious fact with any agent. But one of the challenges with radium is that, because it is not a remission-inducing therapy (Prostate-Specific Antigens don’t go down and tumors don’t necessarily shrink, even when there is some clinical benefit), its beneficial effects are cumulative. Many analyses of radium treated patients confirm that the clinical benefit comes late, not at the first dose. I think of it as the result of putting down many “layers” of therapy. The challenge with this is trying to match the speed of the therapy to the speed of the disease. If the disease is faster than the benefits of the treatment, you will lose the battle, and probably the war. Thus, if you are going to use a mild treatment like radium, you need to begin it in the setting of mildly symptomatic bony disease. Or, maybe before that time. That’s where this patient is, but while the symptoms are relatively mild, the pace of the disease and performance status decline is not. That’s the rub.
- Some patients have a short window from the development of metastatic disease to symptomatic metastatic disease, but most don’t. My patient’s radium window was very narrow compared to most. He went from being elderly with no metastases and no symptoms, to being elderly with metastases and symptoms and a declining performance status very fast. “Being elderly” played a large role here, so I include that modifier for a reason.
- We may have missed the opportunity to overcome this short window problem with radium. Optimally, if radium has significant antitumor effects against bony disease AND it is critical to get all 6 courses of therapy, we should start it in the ‘earlier’ mCRPC setting, in the asymptomatic or minimally symptomatic setting where we commonly use abiraterone or enzalutamide. Combining radium with abiraterone or enzalutamide appears to be a dead concept, but it shouldn’t be. I have written about the ERA223 study before – a randomized phase III study where abiraterone treatment was given with or without radium-223.1 Results revealed an excess of fractures, and deaths, in patients on the radium arm when compared to placebo. A corrected analysis comparing patients receiving bisphosphonates versus those not receiving them removed this disparity – but we missed the window, and the resolve perhaps, to continue the vetting of this concept. So, arguably, we should repeat the studies and treat everyone with bone-targeted therapies and abiraterone with and without radium and see what, if any, the benefits of this triplet therapy are.
- It “feels” like not much research is happening on radium right now, that it is a treatment that is just “out there” for us if we want, but doesn’t have a tone of creative, progressive, and biology-driven energy behind it. That is too bad because there are a few recent observations that may need to be the attention of such energies.
Ultra-sensitive patient populations may exist. One such population may be those with defective DNA repair. In a recent report from investigators in the Netherlands, it is suggested that patients harboring mutations in DNA damage repair (DDR) have superior outcomes when treated with radium.2 These outcomes may simply be a product of the fact that patients with DDR mutations are simply more likely to complete the treatment. Maybe there is a link – DNA damage from radium + defective DNA damage repair = synthetic lethality. A National Cancer Institute (NCI) sponsored Phase I /II is studying this concept prospectively by combining olaparib with radium-223.
Finally, we haven’t really fulfilled the promise of earlier use. We now have multiple examples of therapies that showed advantages in late-stage disease that was augmented when moved to earlier-stage disease. Abiraterone and enzalutamide both showed modest benefits post docetaxel and subsequently better benefits, in earlier mCRPC and best benefits when given with initial androgen deprivation therapy. Docetaxel itself followed the same pattern. The window for radium in earlier stage disease may have closed. My colleagues and I in the Alliance for Clinical Trials in Oncology had developed a study of abiraterone with and without radium in de novo metastatic disease but its development was scuttled on the heels of the findings from ERA 223. I am not aware of a similar study being done elsewhere, thus radium may be forever relegated to the mCRPC, and not the metastatic castration-sensitive prostate cancer (mCSPC) space.
At the end of the day, we may need to proceed on our own with this therapy. It is there for us and for our patients. Figuring out the ideal case in which to use it to maximize benefit may still be needed. Let me know if you’ve figured it out.
Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Director and Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota
- Smith, M., et al., Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2019. 20(3):408-419.
- van der Doelen, M.J., et al., Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer. Eur J Cancer, 2020. 136:16-24.
Read: ASCO GU 2020: Clinical outcomes and Patient profiles in REASSURE: An Observational Study of Radium-223 (Ra-223) in Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Read: ASCO GU 2020: Prognostic Factors that Affect Survival Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Radium-223
Watch: Changing the Mechanism of Action in The Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Phillip Koo
Watch: Real-World Clinical Outcomes with Radium-223 in Metastatic Castration-resistant Prostate Cancer - Neal Shore