Expert Talks Optimizing ADT in Prostate Cancer

Prostate Cancer

Recent results from the phase III CHAARTED, STAMPEDE, and LATITUDE trials have highlighted various strategies for optimizing androgen-deprivation therapy (ADT) in patients with advanced or metastatic prostate cancer.

“The field has shifted away from a one-size-fits-all approach for ADT to one that is really adapted toward a patient’s disease state,” explained Rahul Aggarwal, MD.

OncLive: Can you provide an overview of your lecture on ADT?

In an interview during the 2017 OncLive^® State of the Science SummitTM on Genitourinary Cancers, Aggarwal, assistant professor, director of the STAND Clinic, Helen Diller Family Comprehensive Cancer Center at University of California, San Francisco (UCSF), discussed maximizing ADT in prostate cancer. In his presentation during the meeting, he also highlighted the success of recent studies of ADT, as well as its future utilization in various stages of disease.Aggarwal: I spoke about ADT for patients with prostate cancer, and, in particular, I focused on some of the recent data that have come out with the use of abiraterone acetate (Zytiga) and some of the new potent androgen receptor (AR)-targeting therapies and how they have really changed practice patterns—especially for patients with metastatic prostate cancer. I focused on those studies and how to apply them in practice.

What are some of the most significant data that we have now?

I did discuss the difference between the LHRH antagonists versus the agonists, the choice of ADT, and what the current data and practice patterns are. I also shed light on the emerging clinical trials looking at earlier use of even more potent therapies—not just in the metastatic setting, but in the earlier disease settings by a chemical recurrence—and localized prostate cancer.There have been 2 hallmark studies that were presented earlier this year looking at the use of abiraterone in conjunction with standard ADT for patients with metastatic prostate cancer. One trial is the LATITUDE study, which is a Janssen-sponsored, randomized, phase III study that looked at abiraterone plus ADT versus ADT in patients who have metastatic prostate cancer with high-risk features—3 or more metastases or higher Gleason grade. It showed a pretty convincing overall survival benefit with the combination compared with standard ADT.

Those data were supported by a second phase III study that was also reported at the 2017 ASCO Annual Meeting. That was an analysis from the STAMPEDE study, which is a large United Kingdom-run study with multiple arms—a sort of adaptive clinical trial design. One of the comparisons that they did was adding abiraterone to ADT versus ADT monotherapy—a very similar design [to LATITUDE]. This study was a little bit more inclusive, as it had a lot of different patient groups—those with high-risk localized cancer, those with node-positive disease, and patients with metastatic cancer. Therefore, it was a little bit broader of a group, but the overall outcomes—particularly in metastatic patients—was similar to LATITUDE, and we see a pretty convincing survival benefit there.

Can you discuss the differences between agonists and antagonists?

For the patients with newly diagnosed metastatic prostate cancer, the standard of care has really shifted toward more intensive therapy. There is still an open question in the field about previous data from CHAARTED and other studies that suggest adding docetaxel to ADT also achieves improvement in long-term survival in these patients. There is still an open question about which agent to choose and whether we can combine them.We have a study that we are doing in biochemical recurrence that is being run through the Alliance Foundation Trials, in which we are using degarelix (Firmagon)—an LHRH antagonist—as the standard ADT backbone in all 3 arms. That study is degarelix alone, degarelix plus apalutamide, and degarelix plus apalutamide and abiraterone—so it’s sort of throwing the kitchen sink at these patients but treating for a finite period of time. We treat for 12 months and then we stop. What we are really aiming for is whether we achieve long-term progression-free survival (PFS) or perhaps even cure some of these patients with biochemical recurrence, which we didn’t think was feasible with ADT alone.

What about other emerging clinical studies this space?

In terms of the difference between the LHR antagonist versus agonist, the reason we chose degarelix is that you achieve a fast testosterone suppression. There are preliminary data that perhaps the prostate-specific antigen (PSA) PFS is slightly better with degarelix versus the agonist. Then, there is a toxicity piece to it that suggests that, particularly for patients who have preexisting cardiovascular disease, there is a possibility that degarelix has a lower risk. There is a prospective study that is ongoing to validate those findings. In the interim, degarelix is certainly a reasonable choice for an ADT backbone, which is why we chose to use it in that study. There is a study being run through the cooperative groups looking at risk stratification. One of the things that we are seeing is that in patients who have excellent outcomes on ADT, the cancer is suppressed, or, perhaps, even PSA undetectable for a long period of time. Then, you get patients on the other end of the spectrum who are higher risk; PSA doesn’t really decline and the disease has a pretty short time to castration resistance. We don’t have a great way of predicting who is going to fall in which category.

Some of the newer genomic classifiers are trying to get at that question. One of our faculty from UCSF, Dr Felix Feng, has looked at a genomic classifier that is call PAM50, which was first developed in breast cancer but has been applied to prostate cancer. You see that these 3 subtypes—luminal A, luminal B, and basal—which we think of in breast cancer literature, may have some applicability in prostate cancer.

Particularly, one of the subtypes predicts for less response to ADT. Therefore, one of the studies that Feng is doing through the NRG Cooperative Group is looking at patients who get salvage radiation therapy (RT) after prostatectomy. Our standard practice there is to add short-course ADT with RT. This is a study randomizing that versus apalutamide, which is another AR antagonist, but is stratified based on genomic classification.

Looking ahead, what does the future of ADT look like to you?

This is really one of the first studies that is prospectively integrating these genomic classifiers into the trial design. This is going to be increasingly common as we think about new studies in the hormone-sensitive space.We will see an increasingly earlier use of some of these more potent therapies. Considering the trends that we have seen with LATITUDE, CHAARTED, and STAMPEDE, we will see that when these therapies are applied earlier, they demonstrate benefit. However, it is not going to be a uniform one. That is what we are trying to predict for those patients who are higher risk who may not have as good of a response to ADT—that is where a lot of the drug development is going to have to happen. Or those who, after a few months of induction hormone therapy whose PSA is not declining as fast as we would like, drug development will have to happen to think about the next wave of therapies.

The flip side of it is, as we use all of these therapies earlier in the disease course, what happens then to the time to progression? When these patients are castration resistant they have already been on abiraterone, enzalutamide (Xtandi), apalutamide, and they have already had their AR pathway potently suppressed. Are we going to see a more aggressive type of cancer emerge in that setting? How do we treat it? These are very relevant questions for the field as we move forward.