IPCC Case-Based Discussion: How Should We Sequence Therapy?

A multidisciplinary audience gathered in New York City for the 5th Annual Interdisciplinary Prostate Cancer Congress. The meeting provided an opportunity for medical oncologists, radiation oncologists, and urologists to review the latest strategies and therapeutic agents available for patients with prostate cancer and fostered discussion to build consensus about best treatments.

Three case studies focused on how best to sequence therapy in prostate cancer were presented by Daniel P. Petrylak, MD, and discussed by a panel that included Robert Dreicer, MD, and Oliver Sartor, MD. The audience voted on the treatment options they would have chosen for the patients whose cases were presented.

Case 1

Petrylak: The patient is a 72-year-old man with a PSA score of 80. A biopsy of the prostate reveals Gleason score 10 adenocarcinoma with small-cell components. A bone scan demonstrates extensive metastatic disease, and a CT scan of the abdomen/pelvis demonstrates three hepatic metastases.

Which of the following treatment options would you recommend?

1. Combined androgen blockade
2. Combined androgen blockade with carboplatin/etoposide
3. Carboplatin/etoposide alone
4. Combined blockade with carboplatin/docetaxel

Case 1. Audience Response*

*Totals may not equal 100%

Dreicer: When you see a patient like this, with hepatic metastases and a hint of small-cell pathology, you worry about a mixed lesion because that is more typical biologic behavior. So, clearly, androgen-deprivation therapy (ADT) is appropriate. Every once in a while, a patient will show up with liver metastases from the adenocarcinoma component, so I think it’s reasonable to start with ADT. I’d probably re-image the patient in eight to 10 weeks, assuming he is asymptomatic. Obviously, if there are symptoms, you’ll start systemic therapy.

Sartor: I’m thinking there are probably two components to the tumor. If small-cell is 80% on the biopsy, that pushes me a bit more toward combined androgen blockade with carboplatin/etoposide.

Petrylak: The patient was treated with combined blockade with six cycles of carboplatin and etoposide up front. His PSA normalized, and a CT scan of the adenocarcinoma showed that his liver metastases went away completely. He was maintained on combined blockade. After one year, his PSA rises to 40 and his liver metastases comes back. He also develops symptomatic bone pain.

Your next treatment choice is:

1. Abiraterone acetate
2. Carboplatin/etoposide
3. Carboplatin/docetaxel
4. Combined blockade with carboplatin and docetaxel

Petrylak: Fifty percent of the audience chose abiraterone acetate, and 39% selected carboplatin and docetaxel.

Sartor: To me, that PSA rise indicates that the androgen axis is still intact. So I feel that bringing an additional way to attack the androgen axis, like the abiraterone, is very reasonable. We don’t have a lot of data in this sort of setting—in fact, we have almost none—and I wouldn’t fault anybody who would go with the carboplatin/ docetaxel.

Dreicer: It still may be that what we’ve seen here is just mostly adenocarcinoma, so if at this juncture he’s symptomatic, I think abiraterone is a very reasonable choice. I probably would again give him four weeks of therapy and see whether or not there’s any clinical response.

Petrylak: The patient was treated with abiraterone/prednisone. On that treatment, his PSA dropped from 120 to 30, but a CT scan shows continued progression of the disease in his liver. Do you think the patient has a small-cell component at this point? Do you think he has an adenocarcinoma?

Your next treatment options are:

1. Carboplatin/docetaxel
2. Oral etoposide
3. Carboplatin/etoposide
4. Irinotecan-based therapy

Petrylak: Approximately 67% of the audience said they’d treat with carboplatin/docetaxel, 17% said carboplatin/etoposide, 10% said irinotecan, and 7% said oral etoposide.

Sartor: Is there a role for measuring chromogranin A or neuronspecific enolase? Would that help determine whether to do a re-biopsy at that point?

Petrylak: I’ve found it to be all over the place, and you can’t really get into a trend. Doing another biopsy is not unreasonable, but at the same point, is it going to alter your therapy that much that you want to delay and arrange for a CT-guided biopsy?

Petrylak: The patient was treated with carboplatin and docetaxel, and responded to treatment. The liver lesions are completely gone, although the cancer did progress into his lymph nodes, so he’s now on cabazitaxel.

Sartor: I’d like to comment some more on carboplatin/docetaxel. We’ve published studies on that, and it turns out from a PSA perspective that it’s really quite an active combination. We were using it second-line and have some patients getting some pretty reasonable responses. Nobody has pursued this because it’s an old drug and old drugs die, but it’s not a bad combination at all.

Audience member: How would a re-biopsy change your decision?

Petrylak: Well, I think that you may not go forth with a small-cell regimen if you saw that the cancer was adeno-dominant.

Dreicer: The optimal time to do that would have been up front, because if you’ve demonstrated a small-cell component, you already know what you’re going to do. And if it was a pure adenoma, you’d also do something different. By the time you go downstream, you’re really talking about palliation.

Case 2

Petrylak: The patient is a 73-year-old male who underwent a radical prostatectomy for a Gleason 9 adenocarcinoma, stage T2N1M0. He undergoes adjuvant androgen blockade because of his positive lymph nodes. His PSA begins to rise from 0.8 to 1, and then one month later it’s 2.3. His bone scan demonstrates no evidence of metastatic disease, and his CT scan of the abdomen/pelvis is negative.

What do you do next?

1. Enter the patient in a phase II study for abiraterone in castration-resistant, nonmetastatic prostate cancer
2. Administer Casodex 50 mg PO QD
3. Start denosumab 120 mg SQ Q month
4. Obtain sodium fluoride PET scan

Case 2. Audience Response

Petrylak: I think the trial is reasonable, but there’s a risk that some patients may be directed away from it because Medicare is paying for the sodium fluoride PET scan on the basis that eligible patients will then be treated with sipuleucel-T. That’s just one of the issues being raised by these sensitive tests that can detect growing cells in the bone marrow or the bone cortex. They may be detecting disease earlier so you can get more of a treatment effect, or is this going to translate into a stage migration? We really do need to evaluate these properly to see if we’re actually doing any good by using these more expensive tests.

Dreicer: I agree that abiraterone on an investigational basis is absolutely the right thing to do. There is at least theoretical rationale that abiraterone may have some meaningful impact. And you have a trial, so that would be the answer.

Petrylak: But what will that mean for the patient if he fails abiraterone? In a retrospective study, Johann S. de Bono, MD, MSc, PhD, [of The Royal Marsden, London, England] looked at his patients who progressed on abiraterone and went on to receive docetaxel. And what he found was that their survival was reduced to about 13 months, and the PSA decline rate was somewhere around 28% to 30%, lower than you would have expected. It’s a small cohort of patients, and it wasn’t a randomized trial, so you have to take that for what it’s worth. But it may imply that you are making these patients resistant to docetaxel, so then what do you do? We don’t have a good answer, but it needs to be followed up as a study.

Dreicer: At least a theoretical rationale is that docetaxel may actually be operationalizing as an androgen receptor-targeted therapy as opposed to a cytotoxic. That’s the issue that’s underpinning this, and that’s theoretically why another androgen receptor- targeted therapy following a first one might be less effective.

Audience member: Isn’t abiraterone approved by the FDA only after docetaxel, and if so, are the insurance companies paying for abiraterone ahead of chemotherapy?

Dreicer: Yes, it’s approved post-docetaxel. With regard to prechemotherapy uses, it’s very regional. About four months ago I started using abiraterone in a pre-chemotherapy setting, and I’ve actually had very little difficulty getting it reimbursed for what I felt were appropriate patients. But I know that there are certain parts of the country where there’s essentially no chance of getting it approved.

Audience member: So who would you consider an appropriate patient for abiraterone before docetaxel?

Dreicer: The patients I will treat typically have rapidly progressive disease but no symptoms. These are patients I would not routinely treat with chemotherapy, but if I had a therapy that was effective (ie, abiraterone), then I would treat them.

Audience member: What has been your experience with response rate to abiraterone after someone was refractory to androgen blockade?

Sartor: Sixty-five percent. The tumors are unequivocally going to respond to abiraterone at a vigorous rate in the secondary hormonal setting. One of the things I’ve noted, though, and it’s more of a question I’m asking the group as a whole, is that when we look at this group of patients and they begin to fail abiraterone and those types of agents, the progression of their disease is very explosive.

Petrylak: That’s the point of the randomized stage II trial that was mentioned before. We may get an answer from that.

Case 3

Petrylak: The patient is a 68-year-old male diagnosed five years ago with a Gleason score 9 adenocarcinoma of the prostate. Two years ago, the cancer became metastatic to bone, and he started combined androgen blockade. When the anti-androgen is withdrawn, his PSA rises to 2 over a six-month period. A CT scan of the abdomen and pelvis demonstrates no visceral metastases, and metastatic disease to bone.

You decide to treat the patient up front with:

1. Abiraterone/prednisone
2. Sipuleucel-T
3. Docetaxel/prednisone
4. Ketoconazole/hydrocortisone

Case 3. Audience Response

Dreicer: This is the classic patient with whom, if one is going to give immunomodulatory therapy, sipuleucel-T is clearly appropriate to discuss. When we don’t have any data, for those patients who get sipuleucel-T and who are appropriate to receive additional therapy, abiraterone is perfectly reasonable. I’m not an immunologist, but immunologists tell me that 5 mg to 10 mg of prednisone, at a basic science level, really doesn’t compel one to think that it would alter an immune response. If I were going to give subsequent therapy, I would use abiraterone and prednisone. I think that’s a reasonable sequencing if one is going to use those therapies.

Petrylak: We’re assuming that testosterone level is castrate. And that’s something that we don’t talk about enough, because I’m running into more and more people, particularly on six-month luteinizing hormone-releasing hormone (LHRH) analogs, that are not bottoming out their testosterones where we think we should. And I think that’s important to check, particularly for urologists.

Sartor: I saw a patient on Wednesday who had forgotten to go back to his urologist and was late getting his shot. I checked his testosterone level and it was 70. So he may not be actually castrate- resistant, but he presented to me as a castrate-resistant case. So I agree with measuring testosterone.

Petrylak: You’ve got to watch out for this, because you can get very easily fooled in missing a primary hormone failure versus somebody who did not normalize the testosterone.

Sartor: I participated in the Eligard (leuprolide injection) trials, and I remember that one patient simply did not suppress. There are these rare patients out there, and you don’t know who they are until you measure their testosterone.

Petrylak: We even thought he was taking a testosterone supplement, like dehydroepiandrosterone sulfate (DHEA).

The last comment to make is if you read the package for every LHRH analog or LHRH antagonist, all say you should be checking testosterone levels. It’s probably a good idea to periodically check testosterone levels, even with a routine patient who is doing well, to make sure you’re getting an optimum decline.

Petrylak: The patient received three treatments with sipuleucel-T. Three months later, his PSA has crept up a bit to 3. His bone scan and CT scan results are unchanged.

You decide to treat with:

1. Observation
2. Ketoconazole 200 mg PO TID
3. Docetaxel/prednisone
4. Abiraterone/prednisone

Petrylak: Approximately 73% said they would observe, 18% chose abiraterone/prednisone, 10% chose chemotherapy, and nobody chose ketoconazole.

Petrylak: I would watch him.

Sartor: Just a quick comment on the early use of abiraterone, and this is something I’ve seen in my older patients. A cautionary issue, and this is anecdotal and not documented in any clear way, is that these patients end up losing muscle mass. I think extreme androgen deprivation might affect the muscles a little bit more than our usual androgen deprivation.

Petrylak: Nobody really knows what the effect of total androgen suppression is going to be on a 20-month basis versus a four- or five-month basis.

Dreicer: When patients come off of a compound like abiraterone, they tell you how fatigued they were while they were on it. There’s no free lunch here. It’s a very important class of agents, but, like anything else, we’re going to have to be thoughtful, not just because of the economics but because of the impact on quality of life.

Petrylak: The patient was, in fact, treated with ketoconazole 200 mg PO TID. Ten months later, this patient had visceral progression, and his PSA rose to 30. He was treated with docetaxel and prednisone.

Petrylak: The important issue is: How do you sequence them? We don’t have biological markers. We’re all doing this based upon moving from lesser toxicity to greater toxicity.

Audience member: You touched earlier on the duration of chemotherapy, and mentioned a guideline of 10 cycles of docetaxel based on the results of a trial. But I would like to know from the panel members what they do in practice if the PSA is continuing to decline and the patient is past the typical number of drug cycles and still tolerating the treatment.

Dreicer: First of all, I don’t follow PSA. When I’m using cabazitaxel, I’m treating patients with advanced disease who are symptomatic. So I use therapy based on symptoms. If the patient comes back and says, “Hey, Doc, I have less pain,” or “I feel better, my appetite is up, I gained a pound or two,” and he’s tolerating therapy, that’s a rationale.

Audience member: What is the minimum and the maximum number of cycles if a patient is responding?

Dreicer: I do the same thing with docetaxel. Like many of us, I treat symptomatically, so with docetaxel I’ll say, “Look, I’m going to try to give you six cycles of therapy, and if you have clinical response, I’m going to stop,” because I’m a believer in a re-treatment paradigm. Cabazitaxel is a different story. Although there is a survival benefit, I’m treating for symptomatic benefit. You don’t need a rocket scientist to tell you when you reach maximal therapeutic benefit and the treatment window says, “If I give you another cycle, I’m defeating the purpose here.” That’s how I use cabazitaxel.

Sartor: I think one of the questions you’re asking is, “Do you stop at 10 if you have a patient who is benefiting?” The answer is I do not. I have patients now on cycles number 18 and 19. I use growth factors according to the FDA guidelines, and I’ve been surprised how nontoxic they are.