Leonard G. Gomella, MD

For this patient, we presented it as low-volume disease. In polling question 4, if the patient had high-volume disease—Jason, as you and Oliver outlined, high-volume disease is defined as visceral metastases or greater than 4 bony metastases, 1 outside the axial skeleton. Would this affect your treatment choice? In other words, would you use abiraterone–ADT [androgen deprivation therapy], enzalutamide-ADT, docetaxel-ADT, apalutamide-ADT? Then would you add on an antigen receptor–targeting agent, enzalutamide-abiraterone plus docetaxel-ADT or other? Dan, when you see these de novo metastatic castration-naïve patients, does the volume of disease play a factor for you relative to your therapeutic options?

 Yes, the volume of disease, the age of the patient, and comorbidities all play an important role. Recently we had the PEACE1 trial, where patients received standard-of-care docetaxel and then were randomized to receive observation or abiraterone. There was a significant improvement in rPFS [radiographic progression-free survival] in patients who received the 2 different treatments, docetaxel and abiraterone. Although we don’t have an abiraterone-alone arm, which would have been wonderful for that study, this is something I’m obligated to discuss with my patients. This is an intricate plan of action because the results were so striking. That needs to be administered. I’m going to look at the age, the aggressiveness, the comorbidities. Abiraterone may not be an appropriate drug for patients with preexisting cardiovascular disease because it can cause hypertension. There have been some reports out of Lenny’s institution [Thomas Jefferson University at Sidney Kimmel Medical College], where there’s an increased rate of cardiovascular morbidity in patients treated with abiraterone who have preexisting cardiac conditions. I’m going to look at my patient in terms of what the long-term goal is, how long they’re going to be treated, what their overall performance status is, and their volume of disease.

 Dan, that’s very well said. I want to make a brief comment that goes back to Lenny. We have data in the castration-resistant setting over taking 1 abiraterone with food as compared with 4 without food. There’s also a Canadian trial that had 2 with food as opposed to 4 without. In each trial, each of which is relatively small, there did not appear to be a difference between the 1 with food or the 4 without food. There are no data in castration-sensitive [disease], but for people whose financial toxicity is substantial, you can cut the price of the drug by 75% and see if you feel like abiraterone may be appropriate.

Dan raised some good points. I don’t want to disagree with Dan, but if you think abiraterone is appropriate and financial toxicity comes to the 4, you could drop down to 1 or 2 abiraterone with food as a poor-man substitute. It’s not FDA approved, not really proven, but something I’ve done in practice when faced with the problem.

We’ve gone to basically standard dosing regardless of body weight and everything with all these oral agents. Oliver, you’re bringing up an interesting point. Has anybody looked at potentially checking PK [pharmacokinetics], abiraterone, or enzalutamide levels to see metabolism and bioavailability and those types of things with PSA [prostate-specific antigen] response?

 That’s been done…. It was published in 

] a couple of years ago in castration-resistant disease. I always bring up a really interesting point because we know the PK of docetaxel is different if there’s testosterone on board. If you want to avoid that, perhaps you wait. In most of these trials, if you have all these trials administer abiraterone within 3 months of starting the initial androgen deprivation therapy, if the testosterone is down to castration levels within a month, I don’t think the PK will make much of a difference. It’s going to be about the same. You probably can get away with it. If you want to formally evaluate that, you’d have to do that at the time that you’re castrating the patient, but it’s probably not going to be any different. It’s a very interesting and an important point.

 Do medical oncologists have any experience with the generic forms? Not necessarily for this patient, but in general, the generic forms of abiraterone vs the Janssen product. Do you have any experience with that, either from using it or how expensive or inexpensive it might be?

 Price is better. It’s hard to evaluate. I know you can go to Costco pharmacy and get some good deals. It’s hard for me to endorse anything beyond that because I can speak to price only. I can’t speak to efficacy.

 There’s the new Kirkland abiraterone. That’s a very interesting point. I haven’t seen much of a difference in price with the generic in my experience. Maybe it’s regional and dependent upon insurance, but I haven’t seen much of a difference.

To expand on that, the problem with generics is you can’t get foundation support. It sometimes works against you if you can’t get that foundation support for a generic. It’s sometimes counterintuitive, but it’s more challenging to write for the generic.

: Jason, we know there’s another branded drug, microparticle abiraterone? Do you have any experience with that?

It’s limited. We’re trialing a granule that you can put in a liquid. But for the 1 you’re referring, the data are limited; not a great experience. I want to go back to PEACE1, though. Dan brought up PEACE1. I’m just a community urologist treating patients, and I’d love to hear the panel’s response. When I saw those data, I was blown away with the rPFS [radiographic progression-free survival] and OS [overall survival] from ESMO [European Society for Medical Oncology], and it was really impressive because this is the first major trial since 2015. Prior to that median survival was 3 years. When you look at the data, the median survival is going past 5 years. In my book, this was is a game changer in how to manage this high-volume patient with mCSPC [castration-resistant prostate cancer]. I’m curious if you guys see it that way, or you still have some questions about it?

A couple of issues. No. 1, the appropriate control should have been ADT-abiraterone because we don’t know if docetaxel adds value. No. 2, and 1 of the reasons I didn’t discuss PEACE1, is that the high-volume subset was the only subset that benefited. If you look at Grain’s presentation, the low-volume subset had no survival benefit. Now the rPFS was better, but we don’t treat people for our PFS [progression-free survival] in general. We want that OS benefit, and that was high-volume disease-restricted funding.

 That was my point before, and it helps us answer the question when a patient comes into the clinic and says, “Doc, I want the kitchen sink thrown at me. I want everything possible done. I want everything up front.” For low-volume patients, there’s no major justification for it. For high volume, there is.

Lenny, I’m going to give you the last word. Dan made some comments when he was talking about what patient comorbidities he was looking at. He mentioned the cardiovascular dysfunction that may be associated with abiraterone. We haven’t talked about it—it’s not really part of this—but when you see a patient’s cardiovascular history, how strongly are you trying to determine whether to use an LHRH [luteinizing hormone-releasing hormone] agonist or oral antagonist?

 That’s certainly an ongoing debate. Our mantra at the multidisciplinary Kimmel Cancer Center is that even if you have a urologist or a GU [genitourinary] medical oncologist caring for you, you need a primary care doctor to organize your overall health. We rely on that primary care doctor to make sure we have good cardiovascular status. Dan mentioned the hypertension and the other problems with abiraterone. So we make sure patients have a good head-to-toe doctor, and we make sure we comanage the patients because I can’t evaluate how significant or insignificant somebody’s cardiovascular disease might be. We’re getting to this phase right now, where men are living longer and longer. These issues are going to become more prominent as men move into many years of being on these agents. We don’t know what the long-term impact is. We don’t use a lot of the oral agent. At Jefferson, we have limited experience with it because we often get into insurance problems in the Philadelphia market with an oral agent. The injectables we never have an issue with, but these are all things we have to look at: quality of life and quantity of life. With all these options, we’re going to be under more burden to customize the treatment for a patient based on all aspects of their life: financial toxicity, comorbidities, their expectations. We’re throwing the kitchen sink at people. Some people want that. Other people say, “I’m good. I’ve got my 18 great-grandchildren. I don’t need all that.” It’s got to be very customized.

Very nicely said, Lenny. A great take-home point to conclude this is toxicity. We’ve always thought about toxicity as 1 big physiologic, but Dave Penson gave a nice talk a couple of years ago about how we need to consider financial toxicity in this age of multiple drugs and the cost associated with targeted agents.

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Daniel P. Petrylak, MD, leads the discussion on approaching treatment of high-volume metastatic castration-naïve prostate cancer.

Treatment options for high-volume mCNPC

 I have a castration-resistant case where all the lesions regressed except a new lesion, and we can’t find anything on conventional imaging in bone. The question is, for a patient who has all the metastatic—4 lesions, for example—and you find 20 on a PSMA [prostate-specific membrane antigen] PET [positron emission tomography], do you change their management? We use the conventional imaging as our way of determining whether they have extensive disease. A PSMA PET is nice. It’s a great thing, but at this stage, we need to understand how we’re going to use that in our management.

 Dan, you’re making a great point because all our level 1 data are built around conventional imaging. As we introduce a PSMA PET—and it’s here—it raises a new series of questions to which our level 1 evidence does not apply. I mentioned the tests as directed therapy, but I may get a PSMA PET scan. This guy may not have 1 lesion to the bone, and he may have 14. Then it becomes a whole different scenario. As we gain new imaging insights, we also have to ask new imaging questions and address it with clinical trials to have the best answers.

That’s great. Let’s go around the table. Oliver, you said you’d consider PSMA. Obviously, 69, ECOG 1 is in retention, which is fairly active. Jason, given that he’s got conventional imaging and low-volume disease, would you push for molecular imaging?

Yes, I would. It’s coming, and we’re getting into a space that we don’t have data on. Based on the STAMPEDE data, which showed a significant improvement in overall survival, over 30%, I’d give localized therapy to this patient and then probably transition to novel hormone therapy. The issue with PSMA and finding more bone lesions is that, as Oliver said, it’s up for grabs. It’s hard to apply the old literature to this new imaging. But of what we presented, and the case that’s there, I’d offer them localized therapy based on STAMPEDE.

Also, I’d like to bring up for the audience SWOG S1802. You talk about historically treating advanced prostate cancer. There’s a major US trial looking at radiation therapy or even surgery. It’s crazy to think that we could potentially be operating on advanced disease and removing the prostate. The key is that we’re moving away from single modality therapy and clearly moving into multimodality therapy. How do we apply it with this new imaging? I guess we’ll have to wait for Oliver and Dan to create some great trials to make that connection to the past.

Your point is well taken relative to this SWOG trial because we’re finally moving forward in these patients with high-risk, high-grade localized prostate cancer, or in this case, which seems to be an oligometastatic disease. To me, that is the way it’s moving, given that we do have better systemic therapies beyond ADT [androgen deprivation therapy]. Oliver’s point relative to how we incorporate hereditary germline and somatic testing isalso going to be key as we launch into this era of precision medicine.

A panel of experts in prostate cancer examine the use of conventional imaging and PSMA PET/CT and the impact on their approach to the management of mCNPC.

Role of conventional imaging vs PSMA-PET in mCNPC

 Editorial Council, is chairman of the department of urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia.

Since the pioneering work of Huggins and Hodges was first published nearly 80 years ago in 

 (1941; 1:293–7), the management of metastatic prostate cancer has relied on primary androgen deprivation therapy (ADT). Reducing the circulating levels of androgens is the foundation for all treatments, from newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) through the late stages of metastatic castration-resistant prostate cancer (mCRPC). While ADT usually slows prostate cancer progression, metastatic prostate cancer remains a fatal disease in need of improved therapies.

The phase III ARCHES trial evaluated enzalutamide (XTANDI) plus ADT in men with mHSPC. The study met its primary endpoint of improving radiographic progression-free survival versus ADT alone. ARCHES is another example of the trend in combining agents to improve outcomes, a concept known as “therapeutic layering.”

Enzalutamide plus ADT improves rPFS in hormone-sensitive PCa

Therapeutic layering, first described in the treatment of mCRPC, adds one or more agents onto an existing therapy 

 The concept is now becoming commonplace in the initial treatment of newly diagnosed metastatic prostate cancer.

Other recent examples of therapeutic layering in which agents are added to ADT in mHSPC include the CHAARTED trial (adding docetaxel), the LATITUDE trial (adding abiraterone [ZYTIGA]/prednisone), and the TITAN trial (adding apalutamide [Erleada]). Results from both CHAARTED and LATITUDE demonstrated improved overall survival with the combination therapy. Preliminary results from TITAN have also shown improved survival. ARCHES has shown the benefit of layering enzalutamide with ADT.

The recent trials using therapeutic layering are redefining how initial mHSPC is managed. Historically, the addition of nonsteroidal antiandrogens (eg, flutamide, bicalutamide) to ADT regimens represented the first therapeutic layering attempts, but only minor improvements in long-term outcome were seen with this combined androgen blockade (CAB) approach. CAB outcomes were inferior to those of recent trials that support the combined use of ADT with chemotherapy or next-generation androgen receptor pathway blockers in mHSPC.

Docetaxel and abiraterone are now part of mHSPC guidelines such as those from the National Comprehensive Cancer Network. With the likely approval of enzalutamide based on the ARCHES trial, we will have one more agent available to perform therapeutic layering to improve outcomes in men with newly diagnosed metastatic prostate cancer.

Articles

"Therapeutic layering... is now becoming commonplace in the initial treatment of newly diagnosed metastatic prostate cancer," writes Leonard G. Gomella, MD.

Therapeutic layering in advanced PCa: Another win

Editorial Council, is chairman of the department of urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia.

It is well established that African-American men are more likely to develop prostate cancer and experience higher mortality than other ethnic groups. Most research has focused on determining the causes of prostate cancer in this high-risk group. Numerous studies have evaluated socioeconomic issues, participation in screening, disparities in care for early disease, lifestyle issues, dietary factors, obesity, physical activity and others to identify potential causes.

However, these studies have often been conflicting and inconclusive. While genomics and other biologic analysis are a relatively new focus of these investigations, the complex interactions among all of these factors that may cause prostate cancer remain incompletely understood.

Two provocative studies reported at the 2018 ASCO annual meeting provide additional insight into prostate cancer racial disparities in a different group of patients, namely men with advanced prostate cancer who participated in a variety of clinical trials. In a 

 of these trials by Halabi and associates, the relative risk of death was found to be 19% lower for African-American men than for Caucasian men.

 of 100 men balanced by race reported by George and associates using abiraterone acetate (ZYTIGA), progression-free survival was identical in African-American men compared with Caucasians. Surprisingly, PSA declines and the durability of this response was much greater in African-American patients. What is unique about these two studies is the investigation of racial differences in advanced prostate cancer outcomes in the era of newer therapeutic options.

These studies, both based on clinical trial participation, suggest that some African-American men with advanced disease may actually possess characteristics that make them respond better. With these two trials engaged in ongoing molecular analysis of some of their cohorts, genomic and single nucleotide polymorphism analysis should provide further insight into the optimum management and safety profiles of these advanced prostate cancer therapies.

Previous studies that have identified unique biomarkers with significant differences in expression by ethnicity suggest there may be different molecular pathways that lead to the development of prostate cancer. These differing pathways may also be found to impact response to advanced prostate cancer therapy in different races.

These two studies may not provide insight into the primary causes of the racial disparities in prostate cancer. However, they do provide hope that when treated for advanced prostate cancer, the outcomes in African-Americans appear to be at least as good, if not better, than other ethnicities.

"Two provocative studies reported at the 2018 ASCO annual meeting provide additional insight into prostate cancer racial disparities in a different group of patients, namely men with advanced prostate cancer who participated in a variety of clinical trials," writes Leonard G. Gomella, MD.

Leonard G. Gomella, MD

Articles

Treatment options for high-volume mCNPC

Role of conventional imaging vs PSMA-PET in mCNPC

Therapeutic layering in advanced PCa: Another win

Rethinking race and prostate cancer outcomes