Management of mCRPC: Radium-223

Jorge A. Garcia, MD, FACP: It’s important to recognize that you’re going to have different pockets of practice in America. When you think of ALSYMPCA and you think of the importance of radium 223 dichloride, I tell my patients that what I want to do for them in the context of their progression is to actually expose them to any life-prolonging agent that we have developed. If you look at the life-prolonging agents in metastatic castration-resistant prostate cancer, it’s very simple. There is oral agent No. 1; oral agent No. 2; ABI-ENZA [abiraterone-enzalutamide] or ENZA-ABI [enzalutamide-abiraterone], however you think of those 2 oral agents. You’ve got docetaxel, you’ve got cabazitaxel, you have radium 223 dichloride, and you have sipuleucel-T. There is no other FDA-approved agent that has led to survival improvement in that context.

The recent data using olaparib as a PARP inhibitor, for men with metastatic castration-resistant prostate cancer with DNA-repair deficiencies, are the data that Maha Hussain presented last year at ESMO [European Society for Medical Oncology Congress] 2019 and now are published in the New England Journal of Medicine. A PARP inhibitor, in that case olaparib, was used in that patient population compared with those who went on to receive an oral agent in the sequential manner—meaning you got an oral agent before, you progressed, and you went on and got randomized based upon on your DNA-repair deficiency to either get PARP or an oral sequential agent. PARP therapy led to not only a radiographic progression-free improvement but also survival improvement.

We also have the data looking at cabazitaxel against oral sequential therapy, which are the data also presented last year at ESMO and now published, clearly demonstrating that sequential oral therapy not only doesn’t improve survival but actually could cause detriment to the vast majority of patients who receive sequential therapy. I would argue that if someone has seen docetaxel-based chemotherapy, has seen 1 oral agent, my approach would be to sequence those patients to a cabazitaxel-type approach, which is in fact the second-line cytotoxic of choice in North America, based on the TROPIC trial and certainly based on the PROSELICA data looking at different dosing of 20 or 25 mg/m2 given every 3 weeks. Most of us do recognize that if you have seen docetaxel in the frontline cytotoxic-type treatment for castration-resistant metastatic patients, then the second chemotherapy of choice should be docetaxel.

When you look at that, I think this patient actually could have gone either way—could have received an oral agent or could have received radium 223 dichloride. Perhaps let me pick on radium 223 dichloride a bit more if I can. There’s a misconception in our practices in the United States that if I were to use radium 223 dichloride, I may not be able to give cytotoxic chemotherapy after because of the potential for bone marrow suppression. That’s really a myth, in my opinion. Look at the AE [adverse event] profile in the ALSYMPCA data and, for that matter, in the expanded-access data from the European region and the expanded-access data from the US that was published several years ago with Oliver Sartor. You clearly see that the incidence of grade 3 and 4 neutropenia and grade 3 and 4 anemia, or neutropenia and thrombocytopenia for that anemia, is 1% when you have never seen chemotherapy, which is chemotherapy-naїve. Bu, if you have seen chemotherapy and then go on docetaxel, you have an increase around 2% to 3% to 4%.

When you look at that data, I remind you that the incidence of grade 3 and 4 neutropenia when you do docetaxel in the SWOG 9916, although that’s obsolete today, and the TAX 327, is more than that. I don’t think the decision to use radium 223 dichloride should really be based on the concern that if you give radium 223 dichloride before chemotherapy, you may not be able to get chemotherapy. Or if you do, then you’re going to have an increased toxicity with regard to marrow suppression and/or vice versa, that if you get chemotherapy before, then you may not be able to get radium 223 dichloride because of the ablation in the marrow that chemotherapy may have left in the frontline or second-line space.

One of the challenges of ALSYMPCA, and specifically of radium 223 dichloride to some extent, is that it’s interesting because this is an alpha emitter. I have to disclose that I have never used in my career a beta emitter, so this is not to compare that with an alpha emitter. But alpha emitters are big, thick particles that have a short penetrance and work through the microenvironment in the bone marrow. Although the true MOA [mechanism of action] of radium 223 dichloride has really not been elucidated, it can lead to double-strand DNA breaks.

When you look at that, 1 of the challenges is not only did it improve survival but that it faces some of the similar challenges in the sipuleucel-T phase, for which you cannot rely on PSA [prostate-specific antigen], objective progression, or an objective finding. This is because in the trial, scans were not mandated. They were done ad hoc at the discretion of the treating provider. For PSA, we saw only about a 15%, 16% PSA reduction in the patient population. You’re not really picking ALSYMPCA or radium 223 dichloride with the expectation that you’re going to see a PSA decline or the expectation that you’re going to see a change in the findings of the scans. It is a problem because we are accustomed to and like to see PSA reductions. We also are traditionally are accustomed, as providers, to actually get an oral therapy or cytotoxic therapy and follow you with serial imaging scans. Traditionally we tend to do scans every 3 to 4 months. In my practice we do it every 3 cycles on chemotherapy.

When you look at that, I don’t know when to scan patients. I tend to scan my patients every 3 cycles of radium 223 dichloride even if they don’t have symptoms, because I want to make sure they’re not progressing in visceral organs. I tend to actually start therapy, get scans 3 times a month. I don’t know the impact of radium 223 dichloride as an alpha emitter in a technetium-99m bone scan, and I certainly don’t know what to expect with lymphadenopathy and so on, especially if it’s less than 3 cm, which was part of the inclusion criteria of the trial. But I like to scan patients in the middle and at the completion of radium 223 dichloride. I know so many of my colleagues in the United States will say, “Jorge, no, we can actually just get 6 cycles and then scan the patient at the end of the 6 cycles and not even check their PSA.” I don’t tend to do that. That’s just my own practice.

What is important for the audience is that I don’t make decisions on that PSA. PSA changes when you are castration resistant, and it’s not a reliable way to manage the patient. Perhaps this is with exception that if you elected to start oral therapy with ABI [abiraterone] or ENZA [enzalutamide], I do expect to see a PSA with those agents because they work through these agents, which are AR [androgen receptor] inhibitors. They block AR signaling pathway, where you do it through the adrenal gland, in the case of ABI [abiraterone], or you do it through the AR signaling directly the receptor through enzalutamide. Because they do work through the factor that makes PSA, I would like to see and expect to see PSA reductions.

So that’s my own personal bias. The 3 bigger questions here are if you don’t see a PSA reduction on oral therapy, should you stop and when do you do so? The second is if you see declines but you see transient increases over time, which is what I call the drifter, then when did you make that decision to say it’s time to stop if the patient is asymptomatic, feeling well clinically, and radiographically is not progressing—which is sort of COU-AA-302 and PREVAIL for that matter? What about for those patients who have intractable PSA, basically have 0 PSAs or PSAs absolutely down on oral therapy but at some time they actually develop progressive disease.

There is a thought that some of these patients, a small percentage of patients, may in fact be developing neuroendocrine or a small cell phenotype, mostly neuroendocrine disease or poorly differentiated carcinoma. We didn’t know the answer to that, but I think it’s fair to say that however you define your sequence, you have to pay attention to what you’re going to use to make the treatment decision, to continue, to stop, or to move on to a new treatment. PSA alone should not be used. It’s how do I feel, what my scans tell me, what is my PSA doing, and what are the goals of that treatment in the way we selected and why we selected that therapy up front.

If you were to pick sipuleucel-T or ALSYMPCA with radium 223 dichloride expecting that you’re going to have PSA climb, that’s not the right way of thinking. If you’re selecting all these agents because of survival improvement, then you have to collectively start thinking about what else you are paying attention to: quality of life; patient-reported outcomes, which are very important for us; symptomatic progression; radiographic progression; serological progression; and so on. The field has changed so much that genomics are part of what we do.

For instance, go back to the history of this patient. This patient was genomically tested right up front. He had high-risk disease, had a high PSA, and had a group 4 disease, and he went and had a germline mutational test. Why? Well, if you look at the NCCN [National Comprehensive Cancer Network] Guidelines, we clearly have drastically changed how we think of men with prostate cancer: outside family history, Lynch syndrome, BRCA1 and BRCA2 mutations, my mom and my sister had ovarian cancer. If anything raises a red flag for you as a clinician, there may be an element of a familial syndrome; that is 1 thing. But most patients who are walking in the office with metastatic disease—and for that matter patients who also have high-risk prostate cancer, even if they could be cured—have a significant risk of harboring a germline mutation. That’s why the standard practice for us in the United States is to do germline testing.

Transcript edited for clarity.

Case:A 69-Year-Old Man with Advanced Castrate Resistant Prostate Cancer

Initial presentation

• A 69-year-old man presented with intermittent back discomfort and loss of appetite
• PMH: hyperlipidemia controlled on a statin, no known family history of cancer
• PE: DRE revealed asymmetric, boggy prostate; otherwise unremarkable

Clinical Workup

• Biopsy with TRUS showed adenocarcinoma of prostate
  • Stage T2N0M0
  • Grade group 4
• Germline genetic testing: MLH1, MSH2, MSH6, PMS2, BRCA1/2, ATM, PALB2 and CHEK2
• Chest/abdominal/pelvic CT scan showed no evidence distant metastases or lymph node involvement
• Bone scan was negative
• PSA 24.9 ng/mL

Treatment and Follow-Up

• EBRT + ADT was started
• Follow up at 6 months, PSA 11.2 ng/mL
• At 12 months PSA 18.6 ng/mL
  • Patient reported increasing back discomfort and difficulty walking
  • Bone scan at that time showed multiple vertebral lesions at L3/L4
• Treatment with radium-223 dichloride was initiate
  • 6 infusions were completed, treatment was well tolerated