Evan Y. Yu, MD

: One thing I discuss is that there are 6 regulatory approved agents in the United States that lead to a survival benefit for patients with metastatic castration-resistant prostate cancer. If you consider that patients who have microsatellite instability can receive pembrolizumab—that does happen in maybe around 5% of men with metastatic castration-resistant prostate cancer—that could add a potential seventh option for select patient populations. Pembrolizumab, as we know, is a PD-1 antibody that leads to many improved outcomes across many disease states. For an unenriched population with prostate cancer, there are ongoing trials in combination and in select populations. So, we still have to see, but certainly for microsatellite instability that drug can be used as well.

I think another exciting area in metastatic castration-resistant prostate cancer is the concept behind finding DNA repair mutations. This includes 

. This patient did undergo germline testing, but you could develop somatic alterations as well. That can happen in around 23% of patients with metastatic castration-resistant prostate cancer. About half of those patients in the studies had germline alterations. But biallelic alterations that are somatically occurring happen as well.

Now, when one has a DNA repair alteration, that might make them exquisitely sensitive to agents like PARP inhibitors. The PROfound trial recently showed an important progression-free survival benefit with the addition of a PARP inhibitor, olaparib, for men who have metastatic castration-resistant prostate cancer and DNA repair deficiency. We’re waiting to see what the FDA says, but that could come out as soon as this is posted. We’ll see. It could be very soon. But I anticipate that’s another treatment option to come.

And obviously there are many other exciting treatments. I think another thing that’s around the corner is novel radiopharmaceuticals—radioligand therapies, theranostics, as one might say—that are targeted towards highly-expressed proteins on prostate cancer like PSMA [prostate-specific membrane antigen].

For instance, lutetium is another radiopharmaceutical tagged to a small molecule that can find PSMA on prostate cancer cells. The randomized phase 3 VISION trial has completed accrual, and we’re waiting for results. Obviously, there are many other exciting areas that are being explored in prostate cancer, and I could go on and on forever, but those are some of the things that I think are right around the corner.

Case: A 66-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

A 66-year-old man presented with increasing difficulty walking and sleeping on his back due to lower back and hip discomfort

PMH: hypertension, medically controlled; no known family history of cancer

PE: DRE revealed a nodular prostate; otherwise unremarkable



Biopsy with TRUS showed adenocarcinoma of prostate

Chest/abdominal/pelvic CT scan showed no evidence distant metastases or lymph node involvement

EBRT for 8 weeks + neoadjuvant concurrent, and adjuvant ADT for 2 years

At 6 months post-ADT follow-up; PSA 5.9 ng/mL

Patient reported continued back discomfort, difficulty walking and loss of appetite

Bone scan showed multiple lesions in the right femur and pelvis

Abiraterone + ADT was initiated for 1 year

Patient complained of increased bone pain in right femur

Treatment with radium-223 dichloride was initiated; 6 infusions completed and well-tolerated at post-infusion follow-up

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Rapidly Expanding Options in mCRPC

 Another thing that I didn’t previously discuss is goals of therapy with this patient. For every patient who I see with cancer, and especially those who have a life-threatening cancer—those with an incurable cancer like this patient—I certainly discuss goals of care.

I’m very forthright in counseling the patients on what the goals of our treatment are. If they’re somebody who can potentially be cured of the cancer, that’s always the goal if we can accomplish it safely and with good quality of life. However, if that’s just not possible, I let the patient know that. I talk to the patient about that. I always ask the patient if they want to know about prognosis. I don’t want to surprise anybody with numbers. Most patients do want to know their prognosis, but if they don’t, I respect that as well.

I generally do lay out what our goals are in advance, whether this is a curative therapy or whether this is a palliative therapy. But in prostate cancer, in particular, I emphasize that even palliative therapy can be used for many years.

I think it’s very important to give patients a prognosis, or some sort of a time frame they can think about and work with if they’re interested in that. The reason is so they can do good life planning, family planning as well. They can also feel reassured. We have many good treatments available. Generally, the course of the disease and the natural history of some other cancers are that they are more aggressive.

Our patients with prostate cancer can live for many years. It’s helpful for them to know that, and it’s helpful for them to know that there are many other treatment options that can be used down the road to help them accomplish their goals.

Setting Realistic Goals With Palliative Therapy in mCRPC

 Unfortunately, we’re facing challenging times right now. Obviously at the forefront of everyone’s mind is COVID-19 [coronavirus disease 2019]. That has significantly affected oncologic practices across the country, and the world. Being a part of a large comprehensive cancer center, many clinical trials have been put on accrual pause to limit extra visits for the patients and also to limit touch points for our clinical and research staff. I think that has been a challenge, and hopefully will be a short-term issue. We’re starting to come out of our darkest time with COVID-19, and things are starting to ramp up again. I know our center is slowly starting to open up some clinical trials.

There are many other considerations. This includes hospital beds, and ICU [intensive care unit] beds, and ventilators, in particular. Our center has made a real effort to try to limit hospital admissions of patients who don’t absolutely need to be admitted. That includes considerations of inpatient regimens, clinical trials with inpatient regimens, and even the thought of administration of drugs that have high potential for toxicity that might lead to the patients requiring inpatient admissions to the hospital.

This really affects how we think about cytotoxic chemotherapy agents. In some diseases, the myelosuppression can be very pronounced and very long-lasting. And febrile neutropenia risk is very high. We’re fortunate in prostate cancer, where that risk is not as high with single-agent docetaxel or cabazitaxel chemotherapy. However, it still happens, and it needs to be a consideration.

In my practice, it is certainly a discussion that we have. We are concerned that myelosuppression might increase a patient’s risk of COVID-19. And in that situation, when we have good alternative treatment options, we’re discussing this with the patient. And oftentimes, we’re choosing other treatment options.

So if we were to insert the COVID-19 discussion into this patient’s case that I just presented, I already find enough reasons to use radium-223 and to save docetaxel for later. But another consideration would be that I think the myelosuppression that radium-223 causes is at a much lower level and is a much lower risk than with a chemotherapy like docetaxel. And with that consideration, I think that emphasizes that this patient probably gained the best treatment at that time with radium-223.

There is one issue that wasn’t discussed in this case, and that’s the use of bone protective agents. We all know there are very strong data that support both denosumab and bisphosphonates for use to prevent skeletal-related events and the symptomatic skeletal events in those who have bone metastatic cancers. Certainly, that includes castration-resistant prostate cancer. There are also data for use of these agents in patients who might be at high risk for osteoporotic fractures.

Certainly, men treated with androgen deprivation therapy for prostate cancer are at higher risk of osteopenia and osteoporosis, and there are data to show that use of these agents can prevent osteoporotic fractures.

There are also some data from some database and retrospective analyses that show that these agents don’t cause antagonism with radium-223 and may be beneficial in combination. So that is a discussion I would have with this patient. I would personally add either a bisphosphonate or denosumab in that setting. I would probably use denosumab in this situation.

Significant Impact of COVID-19 on the Treatment of mCRPC

 In my mind, if I was taking care of this patient, the 2 drugs that I really would have considered would be docetaxel or radium-223. I think that the decision there comes down to many pragmatic factors. I can give docetaxel to somebody who is either asymptomatic or symptomatic. I prefer to give it to someone who is symptomatic and has metastatic castration-resistant prostate cancer. This patient was symptomatic, so it would have been reasonable to offer this therapy.

Radium-223 must be given to a patient who is symptomatic. When I think about the timing of these agents, it’s very clear that if you give radium-223 earlier—it’s 6 doses once every 4 weeks—you’re more apt to get all 6 doses into the patient. There are some data that shows that is associated with better survival outcomes. It’s hard to know whether that’s driven by those 6 doses, getting them all in, or whether that’s driven by the patient having a better prognosis. But it’s very clear that those who get 5 or 6 doses in seem to do better than those who get fewer doses in.

Now, that being said, there are a lot of practical considerations. If you give radium-223, you have to get insurance preauthorization. There are rules in regard to what the absolute neutrophil count, hemoglobin count, and platelet count should be. You can’t have visceral metastases. And for those practical reasons, patients’ counts are usually better earlier in the disease course. That’s because they haven’t yet received cytotoxic agents that might cause chronic myelosuppression. It’s also because prostate cancer can infiltrate the bone marrow. If it takes up space in the bone marrow, some patients can be suppressed due to disease involvement in the bone marrow.

That’s one of the challenges. For an agent that requires insurance preauthorization and has clear requirements and limits, you can’t have visceral disease, you have to have certain counts, it makes sense, pragmatic sense, to give it earlier rather than later. If I give it later after docetaxel, they’ve already had chemotherapy and that could be associated with myelosuppression. Well, the visceral disease tends to develop later in the disease course and that might prohibit use of radium-223. You know they might have marrow involvement that would lead to counts being inhibited.

There are no data that definitively shows that radium-223 should be given before docetaxel and that leads to a better survival benefit. But if you live by the theory that my goal is to help my patients live as long as possible with the best quality of life as possible, and to use as many of the treatment options as I can that prolong survival, then I have to think about just pragmatically taking all of these considerations into account. That’s why I like to use the radium-223 rather than docetaxel in this patient in that situation.

Additionally, the toxicities are low for radium-223. It could cause some myelosuppression. Since it’s degraded and excreted from the body rather than metabolized by the liver or kidney, it can go into the small bowel and can cause some diarrhea. But generally speaking, the toxicities are less than what is seen with docetaxel. In real-life practice, I haven’t seen more toxicities than what one would see when reviewing the randomized phase 3 ALSYMPCA trial that was published back in 2013. There have been some subsequent publications that show long-term safety to not be a concern as well either. Some people worry about giving radiopharmaceuticals and the long-term risk of developing a leukemia or a myelodysplastic syndrome, but we really haven’t seen significant challenges with that.

One thing I’d like to emphasize, that I mentioned earlier, is that it makes a lot of sense when a patient progresses on 1 line of therapy to not keep pressing down on that same pressure point.

For instance, if a patient progresses on abiraterone and you give enzalutamide, the results are not ideal. And, vice versa—abiraterone after enzalutamide. That’s because they’re all working via that androgen axis.

I mentioned that changing mechanism of action makes a lot of sense. This is a unique mechanism of action, as radium-223 sits on the same column of the periodic table as calcium. Therefore, if you think about it, calcium incorporates into bone. Prostate cancer, being a bone-predominant disease, causes osteoblast metastases, where there’s a lot of bone turnover. Calcium can sit in those areas. Likewise, radium can incorporate into those areas. It basically is an alpha-emitting radiopharmaceutical and has very potent kill. It can induce double-strand DNA breaks in the cancer without a lot of spread. So it doesn’t have as much myelosuppression as some of the older radiopharmaceuticals, like samarium-153 or strontium-89. So again, it brings a unique mechanism of action that fits with the biology of prostate cancer.

Evan Y. Yu, MD | Authors

Articles

Rapidly Expanding Options in mCRPC

Setting Realistic Goals With Palliative Therapy in mCRPC

Significant Impact of COVID-19 on the Treatment of mCRPC

Pragmatic Considerations for Early Radium-223 in mCRPC