Charles Ryan, MD

CSPC [castration-sensitive prostate cancer] is maybe a slightly different biological entity from CRPC [castration-resistant prostate cancer]. The way I think about it is that CRPC is really an evolved cancer. The term I’ve used my whole career is 

. That’s basically just a fancy term to say that the more that we apply treatment to this disease that we’re not curing, the more the disease is able to evolve biologically. It just goes to show why CRPC is going to be a potentially more aggressive entity.

What’s really going on there? I think there are a number of factors that come into play. First, this patient had metastatic disease at the time of diagnosis. This is not a person who had a screening PSA [prostate-specific antigen] test and had his prostate removed whose PSA level rose a year later. This is somebody who began to have pain in his back and was found to have metastatic prostate cancer.

Right there you know that this disease is probably more aggressive. In fact, we’ve shown that people who present with metastatic CSPC, for example, tend to have more of the basal subtype of prostate cancer than the luminal subtype, which is more of your typical adenocarcinoma that we see in the localized setting. When people develop from CSPC to CRPC, and in particular when people develop abiraterone-resistant disease, we see a lot of really interesting and challenging genomic alterations: loss of the 

, which is probably the most important tumor suppressor gene in all of oncology; loss of retinal blastoma 1, or 

, is very common in that transition. And 

 is a suppressor of the cell cycle. If that is lost, you get the entity of uncontrolled cell cycling, which leads to tumor growth. It might be 1 of the reasons why chemotherapy is effective in that setting, because that’s essentially what we’re targeting with chemotherapy.

There are other aberrations as well, such as loss of 

, which has been known about for a long time. It’s not very common in localized disease, but it’s quite common—in about two-thirds of patients—in metastatic CRPC.

A lot of us spend a lot of time thinking about the biology of this disease and trying to figure out whether we can develop or invent a more targeted approach that hits these mechanisms. As the science continues to advance and continues to work, the need for that science is continuing as we see patients surviving longer, because patients are getting more treatment up front, and then those who develop recurrent disease are going to have more resistant disease. It’s almost an irony. They’re going to live longer, but their disease may be more resistant when it does develop or progress.

The PARP inhibitors and DNA-repair alterations are, of course, an important observation that I touched on previously. Also, I should say that the other reason we should be sequencing tumors is for those rare instances where a patient had microsatellite instable [MSI] prostate cancer, or MSI-high disease.

In a study like this, I would want to know when he’s developing CRPC. I would want to know if he’s developing MSI-high disease. Because if he is, there’s a high likelihood of benefit from immunotherapy. And we’re seeing even complete responses to patients receiving immunotherapy who have MSI-high disease.

This is complicated. It’s actually a really fascinating science and biology, and it’s a real clinical and translational science for us to figure out how we can integrate new therapy into this complicated genomic environment of the transition from CSPC toward CRPC.

In summary, CRPC has gotten to be quite complicated. We have a number of therapies available with a number of mechanisms of action: taxane chemotherapy, AR-targeted drugs, radioisotope immunotherapy, and now the PARP inhibitors. How to use these therapies and how to sequence them are not fully worked out, but there are some highlights that I’ve pointed out here that demonstrate when one might wish to use a therapy at 1 point in the disease course versus another point in the disease course.

As an investigator into new therapies in prostate cancer, I’m actually excited about these findings and look forward to working over the next years in trying to figure out the best algorithm for patients while integrating new therapies and possibly even combinations of the drugs that we’ve discussed today.

Case: A 67-Year-Old Male with Metastatic Castrate-Sensitive Prostate Cancer

A 67-year-old active man presented with intermittent back pain and loss of appetite

FH: the patient’s father suffered a myocardial infarction at age 69; paternal grandmother had dementia; no known family history of cancer

PE: DRE revealed asymmetric enlarged prostate; PE otherwise unremarkable



Core needle biopsy with TRUS showed adenocarcinoma of prostate

Bone scan reveal 3 spinal lesions (T10, L2, L3) and 1 near the left iliac crest

Abdominal and pelvic CT scan showed no other organ metastases

The patient was counselled on treatment options; he expressed concern regarding long-term AR exposure

DOCE + ADT was initiated, 6 cycles were well-tolerated; PSA 6.2 ng/mL

2-year follow-up PSA 10.8 ng/mL; continued treatment regimen

5 months later he reported increasing back pain and difficulty walking

Abiraterone 1000 mg PO qDay + prednisone 5 mg PO q12hr was initiated

Abdominal/pelvic CT showed multiple new small liver lesions, 1 new vertebral lesion and 1 new appendicular lesion

Treatment with cabazitaxel 20 mg/m2 IV q3W + prednisone 10 mg PO qDay was initiated

Videos

CARD Trial: How Does CSPC Progress to CRPC?

A lot of what we know about the toxicity of chemotherapy comes from what we know from the TROPIC study, which was the study that led to the approval of cabazitaxel, and that carried forward on to CARD.

There was not a new signal. There were not new toxicities that were shown to develop in the CARD study. They weren’t really present in the TROPIC study.

In that setting the main toxicity that one needs to be aware of is hematologic toxicity. In fact, that’s really it. In my experience, and the data seem to support it, neuropathy, for example, is not so much worse.

There was a signal about some adverse events and diarrhea in the TROPIC study. That has not really carried forward quite so much, but it does happen. Patients do develop some mild diarrhea. It’s very manageable in the case of cabazitaxel.

For the most part, one can expect neutropenia in patients. And if not adequately managed or prevented, neutropenic fever can occur in anywhere from 5% to 15% of patients. It’s really clinician’s choice about whether they use up-front growth factor support. Keep in mind that the studies comparing the 2 doses of cabazitaxel, 20 mg/m2 and 25 mg/m2, did suggest that there was greater hematologic toxicity in the 25 mg/m2 dose.

If you’re using that dose, I recommend serious consideration of growth factor support. If you’re using the lower dose, you may still get it. You also have the option of choosing 1 of those 2 doses in the clinic at this time.

But there were data that suggest that there really wasn’t much of a difference. For many, 20 mg/m2 is the dose, even though 25 mg/m2 has been used in some other studies.

With regard to other hematologic toxicities, thrombocytopenia can occur. Although grade 3 and 4 were clinically significant, thrombocytopenia is actually quite rare.

Managing AEs in Metastatic CSPC: TROPIC and CARD Trials

This puts us into the situation that was highlighted by the CARD study, a major study published in the 

 within the last year or so. This was 1 where they really wanted to study whether we should do cabazitaxel or another AR [androgen receptor]–targeted drug in this setting.

The CARD study enrolled patients on a 1-to-1 fashion who had previously received a therapy, who had previously received docetaxel, and who had already received either abiraterone or enzalutamide. They were randomized to receive cabazitaxel at 25 mg/m2 every 3 weeks, which is 1 of the dose regimens that we can do, or the other AR-targeted therapy.

In this case, if we were enrolling the patient on the CARD study, he would be randomized to receive either enzalutamide or cabazitaxel. It’s really testing the second AR-targeted drug versus chemotherapy.

CARD Trial: Cabazitaxel After AR-Targeted Therapy in mCSPC 

This patient has reached a critical point. He is resistant to second-generation AR-targeted drugs, and he’s also essentially resistant to docetaxel chemotherapy. Or let’s just say that he has disease progression despite docetaxel chemotherapy.

There are a few options of FDA-approved drugs for patients with CRPC [castration-resistant prostate cancer] that we have not talked about. We’ve not talked about radium 223 dichloride, and we’ve not talked about sipuleucel-T. One might wonder if those are reasonable options for this patient. My approach, and my opinion, based on the data, is that this is not a patient who would be appropriate for either of these treatments.

I do use sipuleucel-T, but I don’t use it in the majority of my patients, and I don’t use it in patients who have symptomatic CRPC, and I don’t use it in patients with rapidly progressing visceral metastases. The reason for that is sipuleucel-T probably exerts some effect on survival and disease progression when it’s given earlier in the clinical course, perhaps as a lower volume of disease.

If I were going to use sipuleucel-T in this patient, I might go back in time to when his PSA [prostate-specific antigen] level was 10 ng/mL and he was beginning to progress after the docetaxel. In that setting he’s likely to do just fine from a symptom perspective for a long time.

Recall that sipuleucel-T does not induce a remission. It does not take PSA down, except in a minority of patients. And it’s not really known to reverse symptoms or shrink tumors. It simply slows the progression of the disease. That may be of significant benefit for some patients, and when we looked at in a phase 3 study across a whole population of prostate cancer patients, we demonstrated that actually it does exert a survival benefit. That’s important, but at this point with the liver metastases, the new boney lesions, and the rising PSA, this is not really a situation where sipuleucel-T is going to be the answer.

Similarly, radium 223 dichloride is a treatment that is really designed for bone disease and is really approved for patients with symptomatic boney disease.

He is not at this point complaining of a significant amount of new pain, but we are seeing new boney lesions develop, and he’s also got the liver metastases. Radium 223 dichloride is a bone-targeted therapy that is not going to have any effect on those liver metastases, and those liver metastases may be the biological process that is most likely to lead lethality for this patient.

We really need to address those liver metastases, and we can’t do that with radium 223 dichloride, and we’re not going to see much benefit from sipuleucel-T, because that window closed about a year ago for this patient.

That leaves us with second-line chemotherapy, and this is a patient with docetaxel resistance who now may benefit from cabazitaxel. Cabazitaxel is a therapy that has regulatory approval for exactly this indication: for patients who have already received docetaxel chemotherapy who are developing disease progression.

Let’s go back and think about some of the cases here and why we might want to choose docetaxel in this setting. What are the factors we want to consider for this patient in terms of his adverse-effect profile, quality of life, etc.

This patient, if we’ve been doing the math correctly, is now 3 years on from the time of diagnosis of prostate cancer. He’s probably about 70 years old. We don’t have any additional history about a cardiac history of stroke or diabetes or anything like that that has taken hold of him that might impact our choice of subsequent therapy. I think that’s good. It leaves a blank slate for us in terms of talking about the adverse effects of treatment.

Here we are in the setting of abiraterone resistance, and based on our case, he’s still on the abiraterone but he’s developing disease progression. The 1 question is, “Should we add chemotherapy to the abiraterone, and is that of really any benefit?” The truth is, there is some emerging benefit that the combination is feasible. There was a study called “abi-cabazy,” where cabazitaxel and abiraterone were completed. And there’s some ongoing work looking at docetaxel-abiraterone combinations.

It’s fair to say that that remains an interesting question, but I wouldn’t say that we have level 1 evidence at this time to say that both therapies should be continued. For the time being, I consider this to be abiraterone-resistant disease, and not 1 where I still need that suppression of the androgen production from the abiraterone. I hope I’m proven wrong in that maybe combination approaches can be demonstrated to be superior to a single agent. But in this setting we’re most likely well served by simply discontinuing the abiraterone, continuing the prednisone, and adding in cabazitaxel.

MCSPC: Treatment After Progression on AR-Targeted Therapy

Back to our case. He has a PSA [prostate-specific antigen] level of 25 ng/mL at the beginning. He goes on ADT [androgen deprivation therapy] and gets chemotherapy. At the end of 6 cycles, the PSA is down quite a bit. It’s not normalized, but it’s 6.2 ng/mL. He’s followed and presumably does quite well because we don’t hear anything from him, and 2 years after that he comes back, his PSA is rising, and he’s on ADT at this time. PSA is 10.8 ng/mL. He’s followed for a bit, and he does ultimately develop worsening symptoms and a rising PSA of 21.4 ng/mL, with a relatively rapid PSA doubling time of about 5.1 months, and he has no new bone lesions that show on imaging.

While this sounds very straightforward, there’s a lot of nuance actually in what’s going on with this case. Should we have followed this patient when he presented with a PSA of 10.8 ng/mL? Should we have started abiraterone on him at that time? Is it appropriate to wait for a patient to develop symptoms before we initiate a new treatment? These are all reasonable questions. However, the use of abiraterone in the CRPC [castration-resistant prostate cancer] setting in an asymptomatic patient is well justified, for 10 years or so, based on the Cougar Biotechnology COU-AA-302 study that led to the approval of abiraterone in that setting. Enzalutamide similarly was demonstrated to have very similar benefits in this setting. So it would have been very reasonable to initiate abiraterone as a PSA of 10.8 ng/mL.

It is a little dismaying that by waiting 5 months, the patient went from being asymptomatic to symptomatic, but that does happen of course. In conversation with patients, many patients choose to wait. They don’t want to be burdened with further therapies. They’re afraid of the monitoring. They don’t want adverse effects. They don’t want the added cost.

Ultimately that is a conversation that takes place between you and your patient about when to consider for therapy. Suffice it to say this patient then starts on abiraterone with a standard dosage of 100,000 mg a day, with prednisone 5 mg twice daily. That is the standard treatment for CRPC. The truth is, we have relatively little data and no real phase 3 data on the efficacy of abiraterone in the setting of CRPC, in which the patient received docetaxel for CSPC [castration-specific prostate cancer], because it remains something of a new clinical space.

But we can still have reasonable expectations for success of this therapy. When I counsel a patient about the use of abiraterone in this setting, I’ll typically offer him an estimate of about a 75% of likelihood that his PSA will go down to 50% or greater and that he’ll be able to be on this treatment for anywhere from 1½ to 2 years based on the depth of that PSA response.

However, in this case he fits into the 25% or 30% or so who may have had an initial reduction in abiraterone, but the PSA continues to rise. He gets a less-than-average benefit from abiraterone in this setting. The PSA ultimately was 30.2 ng/mL, and an abdominal pelvis CT [computed tomography] scan shows multiple new liver lesions. One new vertebral lesion and 1 new appendicular lesion along the spine or the sternum.

This again brings up a little bit of nuance. Recall that when we went back, when his PSA began to rise after the docetaxel, we did a bone scan and saw no new lesions on imaging. It’s very typical that a patient will develop a worsening of disease with a rising PSA but no new bone lesions. That’s what we saw in the beginning. But now when we see this patient developing new boney lesion, that meets our standard academic criteria for radiographic progression, and it also puts him in a position where he is experiencing perhaps more rapid disease progression. Most notably he’s now developed liver metastases, which puts him in a fairly adverse prognostic category.

Even though his PSA is not that high—it’s only 30 ng/mL—we’re seeing a lot of new lesions develop. This does bring up some other concerns that are emerging in the field. Should we biopsy 1 of these liver lesions? While there is very little likelihood that this is not prostate cancer, I believe that over time we’re going to develop a more nuanced understanding of the various histological forms of prostate cancer that can evolve under the treatment pressure of drugs like abiraterone, enzalutamide, or even chemotherapy.

We now know that maybe 20% to 30% of patients in this setting will harbor a neuroendocrine-type disease, or neuroendocrine prostate cancer, which will sometimes be abbreviated as NEPC. This is different from small-cell prostate cancer, which is a very rare disease that is present in maybe 1% of prostate cancer patients. It is generally not associated with hormonal responses and resembles the same types of clinical issues you see when you confront the small-cell cancer in the lung; for example, simply that this is developing in the prostate. The neuroendocrine prostate cancer could be something that is developing here.

We also know through recent publications, for example, that patients developing rapidly progressive disease in the context of what we’d call a relatively low PSA is associated with worse prognosis. And there have been recent publications demonstrating that, showing data on that point, which is something we assumed all along.

Case Overview: Metastatic CSPC Follow-Up and Management

Today we’re going to talk about a case in prostate cancer that illustrates a lot of the current thinking in how to manage this disease as it evolves over time.

This is a 67-year-old man with metastatic castration-sensitive prostate cancer. Here we have a 67-year active man presenting with intermittent back pain and loss of appetite, who has an unremarkable past medical history, and a family history of cardiac disease with his father having a myocardial infarction and a history of dementia but no history of prostate cancer or any other cancers in the family.

He presents to a physician and is found to have, on digital rectal exam, an asymmetric enlarged prostate, but he is otherwise unremarkable on clinical exam. He undergoes a prostate biopsy with transrectal ultrasound, which reveals him to have a T2 prostate adenocarcinoma, grade group 3. And a bone scan done to work this up reveals 3 spinal lesions at T10, L2, L3, and 1 in the left iliac crest. An abdominal pelvic CT [computed tomography] scan showed no other sign of metastatic disease. And PSA [prostate-specific antigen], unsurprisingly, is elevated at 24.9 ng/mL.

Then he is presented and counseled on various treatment options for his disease, which would be considered metastatic. There are a lot of options to consider in a patient like this.

One of the issues in the current era, in 2020, 2021, of course is, do we do anything besides standard hormonal therapy? And it’s quite interesting that for many decades, standard hormonal therapy was the first choice of treatment. I would say that treatment was done in an expectant fashion, where we would start with standard hormonal therapy. When the disease got worse, then we would bring in further therapy. But there are a lot of studies that we can discuss now that allow us to bring in additional therapies earlier in the clinical course that lead to enhanced clinical benefit.

He most likely was counseled around the use of an AR [androgen receptor]–targeted drug such as abiraterone or enzalutamide, both of which have significant level 1 evidence favoring their use in the castration-sensitive metastatic prostate cancer patient; as does docetaxel, which is approved for use in the castration-sensitive metastatic setting, based essentially on the CHAARTED study done in the United States and the STAMPEDE study done in the United Kingdom.

The patient starts docetaxel, plus ADT [androgen deprivation therapy]. This is initiated at 6 cycles, which he tolerates well and his PSA declines to 6.2 ng/mL.

Now just a brief point about what I counsel patients. For most of my patients with high-volume disease such as this, with a high PSA such as this, and especially in a healthy patient who’s relatively young such as this, I do recommend chemotherapy, although I do pick it as not the only choice.

The advantage of chemotherapy in this setting is that it’s a prime period of treatment. It’s actually just 6 cycles of docetaxel, 6 doses of a drug, 6 visits to the clinic, and then that treatment is done. That compares very favorably from a survival perspective, for example, with the use of abiraterone or enzalutamide in this setting as well.

So patients really have a choice. If they want to avoid chemotherapy altogether, they can take enzalutamide or abiraterone, but they are required in that case to take many pills per day. There is ongoing monitoring that is required, and the treatment is somewhat open ended. It’s not done after a period of 16 to 18 weeks, as docetaxel is.

Oftentimes, given those choices, patients will decide, “I’ll take the chemotherapy,” because if you look forward 16 weeks from now, they will be done with all that treatment, and some people find that favorable.

Of course there are some potential risks from the chemotherapy, such as marrow suppression, that one needs to take carefully into consideration. In particular, in your older patients, or patients with prior radiation therapy, or patients with prior chemotherapy exposure, or other factors that might make chemotherapy a little more caution inducing than an oral therapy.

Charles Ryan, MD | Authors

Articles

CARD Trial: How Does CSPC Progress to CRPC?

Managing AEs in Metastatic CSPC: TROPIC and CARD Trials

CARD Trial: Cabazitaxel After AR-Targeted Therapy in mCSPC

MCSPC: Treatment After Progression on AR-Targeted Therapy

Case Overview: Metastatic CSPC Follow-Up and Management

Case Overview: A 67-Year-Old Man With Metastatic CSPC