Kessler Shares Her Perspective on Sequencing Therapies in Prostate Cancer

Elizabeth Kessler, MD

Elizabeth Kessler, MD

Elizabeth Kessler, MD, explained to a group of physicians in a recentTargeted Oncologylive case-based peer perspectives presentation the treatment considerations and decisions she makes when seeing a patient with prostate cancer in the clinic. Kessler, an assistant professor of medical oncology at the University of Colorado (UC) School of Medicine, and a genitourinary oncologist and clinical investigator at the UCHealth Tony Grampsas Urologic Cancer Care Clinic, discussed treatment options with the group in relation to a case scenario of a patient with advancing prostate cancer.

Case

A 64-year-old man presented to his primary care physician with back pain. He had a medical history of prior hypertension. His prostate-specific antigen (PSA) came back at 130 ng/mL.

A bone scan was positive for bone metastasis, 4 were identified within the vertebral body and pelvis. The patient was given a Gleason score of 8. A CT scan showed 3 suspicious lymph node metastases, the largest of which was 1.3 cm. A pelvic bone biopsy showed adenocarcinoma, which was consistent with a prostate origin. The patient had an ECOG performance status of 0.

What is this patient’s volume of disease and risk status?

By the CHAARTED or SWOG study, he has low-volume prostate cancer; by the LATITUDE study, he has high-risk prostate cancer, which comes with some of the volume.

What would the next steps be for this patient?

I think that we have emerging evidence that ADT [androgen deprivation therapy] alone is inferior to a combination of up-front therapy, and what you choose may be influenced by multiple factors such as cost considerations and patient factors. I would not recommend intermittent ADT unless we get a sense of his tolerance of that. Radium 223 [Xofigo] is for a castration-resistant patient.

Why would you not recommend intermittent ADT?

The 2 largest studies show that intermittent ADT is not noninferior. Meta-analyses looking at some of the data may suggest that you could do it intermittently,¹but many guidelines still would suggest continuous, if possible, for patients with evidence of metastases. In patients with nonmetastatic prostate cancer on ADT, then an intermittent approach is completely appropriate.

What are some of the factors that go into your decision making for this patient?

Disease volume, symptoms, and organ involvement. I think some people use age as a deciding factor. I would recommend that we think of patients in terms of their physiologic age, not just their chronologic age, because ECOG and performance status measures that we are used to just miss a lot of things in terms of instruments of activities or daily living. There are plenty of resources in the National Comprehensive Cancer Network senior adult oncology guidelines on how to get a sense of older patients’ physiologic age.

How would you manage the primary tumor in this case? What is the role of local therapy for a patient like this?

A cooperative group study is investigating the role of local therapy in patients with metastatic disease, and those patients could be offered radiation or surgery, although I think they are limiting the number of patients that are enrolled that do receive radiation therapy.

Two studies—STAMPEDE and HORRAD—recently published some of their outcomes for patients who had metastatic disease who received radiation, and it does seem that perhaps in patients with the lower burden of metastases, there may be a survival benefit. The HORRAD study looked at radiation in a much higher-burden metastatic disease population, and they did not see a benefit.²The sense was that perhaps in those higher-risk patients with a lot of metastatic burden, we are not going to see a benefit, but in some of the patients with a more limited number of metastases or who have a nice response to ADT, it might be something to consider.

What did the STAMPEDE trial show?

The STAMPEDE trial is a multiarm trial being performed in the United Kingdom. They are closing arms that have been shown to not be helpful for patients; they are opening new arms as the science evolves. All patients are prospectively enrolled, and many of their analyses are prospectively planned, even if patients aren’t randomly assigned to a trial built to compare, for example, docetaxel versus abiraterone acetate [Zytiga]. But because the patients have similar inclusion criteria, risk stratifications, and treatment assessments, they are able to compare some of these patients contemporaneously.

Looking at the patients who were enrolled into standard-of-care ADT plus docetaxel and prednisone versus standard-of-care plus abiraterone acetate and prednisone, in terms of overall survival [OS], there is no clear difference between these 2 regimens.³This is the best direct comparison we have, although there are some flaws with this study. It wasn’t powered, really, to detect this at the time, but even looking at other analyses of individual studies evaluating these treatments, it does seem that their survival outcomes are fairly similar.

What is the significance of these results?

A bit of historical context…[as] it’s nice to figure where we’re seating ourselves when we’re thinking about the difference between chemotherapy and targeted therapies: The chemotherapy history comes from the CHAARTED cooperative group study and the STAMPEDE trial. In CHAARTED, these patients were all metastatic, and most of them had what was considered high-volume disease. It was originally designed for high volume, and that was defined as either visceral metastases or ≥4 bone lesions, with at least 1 of those lesions being extra-axial, and a third of these patients had a low burden.⁴In STAMPEDE, most patients had metastatic disease, about a third of the patients were node positive, and then a smaller number were M0. Patients that received this therapy had to have at least 2 of the following 3 criteria: Gleason score of 8 to 10, PSA greater than 40, or stage T3. If they met 2 of those, they could enroll on the study and receive standard-of-care ADT plus chemotherapy of docetaxel for 6 cycles, so you don’t continue on; you give a defined treatment cycle.

The patient ranges from these 2 trials are generally a younger median age compared with those studies that looked primarily at abiraterone. The LATITUDE study defined metastatic high risk—so, not necessarily high burden but high risk. They needed to make it more complicated, so there’s more than 3 bone lesions or visceral metastases or Gleason level greater than 8. Patients needed to have at least 2 of these 3 in order to enroll.⁵The STAMPEDE enrollment criteria were very similar, but 1 thing to note in this abiraterone group is that it was a pretty heterogenous population, so a lot of these patients had M0N0 disease, and those patients were required to also receive definitive radiation therapy and 2 years of ADT plus abiraterone. They even included some patients who had biochemically recurrent disease that were relapsed with high-risk features. That was less than 10 patients, but it’s always interesting that they allowed such a diverse population of patients here.

When we talk about abiraterone versus chemotherapy, the populations might be a little bit different, and the data that support it are based off study groups that are slightly different too. But when we look at these STAMPEDE data, which is the best data that we have right now, [endpoints analyzed include] metastasis-free survival; failure-free survival, which included PSA rise, or a biochemical failure, which is why those curves separated, because those patients on abiraterone are not going to have a PSA rise nearly as early as those patients who received chemotherapy; progression-free survival [PFS] in the traditional way that we would define that; and first skeletal-related events. In the areas in which some of the data are reliant on PSA, abiraterone is certainly favored there. This is because these patients would continue on a hormonally driven agent long-term rather than just 6 cycles.

Looking at what came next for these patients is somewhat awkward, because the groups that are randomly assigned to abiraterone are unlikely to start an AR [androgen receptor]—targeted therapy very soon, so the slope of these curves is not dramatically different. A high number of patients went on to receive a next line of therapy. We’re not causing so much toxicity from this first line that these patients are not able to go on to receive additional therapy if they want to. Other factors that I look at here: There doesn’t seem to be a lot of difference between those patients assigned to abiraterone or enzalutamide, many people choose one or another of those agents, and there are still some patients that go on to receive docetaxel too. In the abiraterone group, most of those patients are going on to get docetaxel, which we would think of as a natural next line of therapy after a hormonally directed agent.

[As for] the adverse effects, when looking at chemotherapy, there will be more neutropenia, more hematologic toxicities. You’ll see more LFT [liver function test] abnormalities, hepatic disorders on abiraterone arms. And then, looking at the cardiovascular events, you can see a slight difference between hypertension and some of the other events, but interestingly, the myocardial infarction and dysrhythmias are not much different in the abiraterone group versus the chemotherapy group.

How do you then decide between giving abiraterone and docetaxel treatment with ADT?

Deciding between abiraterone and docetaxel is something that [necessitates] talking with patients about their different concerns and priorities, but cost, I think, does become part of that conversation naturally, as does length of treatment. Abiraterone doesn’t have an endpoint; patients continue on until progression, which could be years in some patients. They often get tired of that; they’d like to just get the 6 cycles, go back to visits every few months for their ADT injection until they have to become more engaged in additional lines of therapy.

Certainly in patients that are more symptomatic or where you’d be concerned that you’d want some rapid response, if they do have any sort of urinary obstruction symptoms—upper tract obstruction, other things there—then it is nice to think about chemotherapy, with the understanding that it’ll be a more rapid response. But abiraterone still has excellent data for activity in patients that even have visceral metastases. I think that it’s not to the breast cancer level, where decisions are made [according to an urgent need for a response], but it is a clinical gestalt.

Are there any additional emerging treatment options?

The TITAN study looked at apalutamide [Erleada] plus ADT in this same setting. Apalutamide is another AR-directed agent, much like enzalutamide, and what they found was that the coprimary endpoint of radiographic PFS, which we think may correlate with OS, was reached. So basically, in this study, the Independent Data Monitoring Committee recommended that patients in the combination group continue but those in placebo be able to cross over to the experimental arm based off these data. This was from a press release earlier this year.⁶

The ARCHES study is similar. This study was using enzalutamide [Xtandi] with ADT also at the start of hormone-sensitive treatment. Patients were randomly assigned to enzalutamide versus placebo, again with a similar outcome of radiographic PFS plus OS. This interim analysis was also recently reported, and patients are also being crossed over to the active treatment arm based on the activity we see here.⁷

The key difference in the apalutamide study versus the enzalutamide study is that patients in this study could’ve received prior docetaxel therapy, so it’ll be one of our earlier studies looking at a sequence of docetaxel and then a hormone agent, which is, I think, the knee-jerk reaction of a lot of folks. There are no data to talk about how to do that sequence. In this study, a small percentage, about 18%, of patients had previous docetaxel.

Regarding the radiographic PFS endpoint, the median follow-up time is 14.4 months, so still pretty early on, but seeing [significant] differences.

In thinking about these high- and low-volume diseases or the docetaxel therapy [subgroup analyses], most things look like they’re favoring the enzalutamide plus ADT combination.

When would you initiate these therapy options?

Most patients started the combination therapy within 1.5 to 2 months. Many of the studies required starting within 3 to 4 months, so each study is a little different.

Some patients will start both together; other times it’s nice to start ADT first to get a sense of tolerance and adverse effects and then add in the next line of therapy, because we know there’s going to be more fatigue there.

In your experience, what is the difference between apalutamide and enzalutamide as possible treatments?

The difference between the 2 agents is that there may be some less CNS [central nervous system] activity of apalutamide. We know that enzalutamide can cause some lowering of the seizure threshold, and also, patients report this kind of fogginess in thinking at times or some sleep disturbances, and the hope was that when apalutamide was developed, we would see less of that. Some seizures still have been reported with apalutamide, although less so. Apalutamide does also have some hypothyroidism, as well as a rash, associated with it, which was reported in 23% to 25% of patients that are on that treatment in some of the other studies, but I haven’t seen it that much.

In most of these enrollment studies, they excluded patients that would be at high risk of seizure, then they did a follow-up study solely of patients at high risk—those that had a history of cerebrovascular accident, transient ischemic attack, other brain injuries—and did not see an increased rate of seizure in that population compared with the other population.

The approach now is that if a patient hasn’t had one of those higher-risk events within 6 or 12 months, then you could safely consider giving enzalutamide in those patients.

What are some treatment options for the next line of therapy when this patient’s disease progresses, and what would affect your decision here?

This patient is now castrate resistant after receiving combination first-line therapy. I think this question opens up a huge can of worms regarding your first-line castrate-resistant therapy choice. The standard approved ones would be sipuleucel-T [Provenge] for patients with minimally or asymptomatic disease and no metastases; certainly radium 223. Most patients generally go on to receive abiraterone, enzalutamide, or docetaxel, and most of the time that’s informed by patient characteristics, patient preferences, and a little bit of what they received first. If they had docetaxel, you’d be less likely to go back to it unless it had been a really long time off.

References:

1. Magnan S, Zarychanski R, Pilote L, et al. Intermittent vs continuous androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis.JAMA Oncol.2015;1(9):1261-1269. doi: 10.1001/jamaoncol.2015.2895.
2. Boevé LMS, Hulshof MCCM, Vis AN, et al. Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial.Eur Urol.2019;75(3):410-418. doi: 10.1016/j.eururo.2018.09.008.
3. Sydes MR, Spears MR, Mason MD, et al; STAMPEDE Investigators. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.Ann Oncol.2018;29(5):1235-1248. doi: 10.1093/annonc/mdy072.
4. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.N Engl J Med.2015;373:737-746. doi: 10.1056/NEJMoa1503747.
5. Fizazi K, Tran NP, Fein L, et al; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer.N Engl J Med.2017;377:352-360. doi: 10.1056/NEJMoa1704174.
6. Janssen Announces Erleada (apalutamide) phase 3 TITAN study unblinded as dual primary endpoints achieved in clinical program evaluating treatment of patients with metastatic castration-sensitive prostate cancer [press release]. Spring House, PA: Janssen Pharmaceutical Companies of Johnson & Johnson; January 30, 2019. www.jnj.com/janssen-announces-erleada-apalutamide-phase-3-titan-study-unblinded-as-dual-primary-endpoints-achieved-in-clinical-program-evaluating-treatment-of-patients-with-metastatic-castration-sensitive-prostate-cancer. Accessed March 19, 2019.
7. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. Phase III study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial. Presented at: 2019 Genitourinary Cancers Symposium; February 14-16; San Francisco, CA. Abstract 68 ascopubs.org/doi/abs/10.1200/JCO.2019.37.7_suppl.687.