Posadas Breaks Down Rapidly Evolving Prostate Cancer Paradigm

Edwin Posadas, MD

Researchers are tapping into new treatment strategies with a focus on quality of life for patients with prostate cancer; however, oncologists still only have a surface-level understanding of the biology of the disease, said Edwin M. Posadas, MD, FACP.

Among the most highly anticipated findings presented at the 2019 Genitourinary Cancers Symposium were the results from the phase III ARAMIS trial, which examined the addition of darolutamide to androgen deprivation therapy (ADT) versus placebo plus ADT in patients with nonmetastatic castration-resistant prostate cancer (CRPC). At a median follow-up of 17.9 months, metastasis-free survival was significantly prolonged with darolutamide compared with ADT alone at 40.4 months versus 18.4 months, respectively (HR, 0.41; 95% CI, 0.34-0.50; P <.0001).

Median overall survival was not reached in either arm, but data showed that darolutamide was associated with a 29% reduction in the risk of death versus the control arm (HR, 0.71; 95% CI, 0.50-0.99; P = .0452).

A central focus of this study was to establish the risk—benefit ratio of darolutamide compared with the FDA-approved androgen receptor (AR) inhibitors enzalutamide (Xtandi) and apalutamide (Erleada). Data from ARAMIS indicated a favorable safety profile, with no increase in adverse events (AEs) and a median time to pain progression of 40.3 months compared with 25.4 months in the placebo arm (HR, 0.65; 95% CI, 0.53-0.79; P <.0001).

Based on these findings, a new drug application was filed with the FDA in February 2019 for darolutamide for the treatment of patients with nonmetastatic CRPC.

“Prostate cancer is a field in evolution right now,” said Posadas, medical director of the Urologic Oncology Program at Cedars-Sinai Medical Center. “Our knowledge of the biology of the disease is moving so fast, but we still have a long way to go.”

OncLive: What were the biggest takeaways you had from the prostate cancer data that were presented at the 2019 Genitourinary Cancers Symposium?

In an interview with OncLive, Posadas discussed recent prostate cancer data and shed light on where emerging therapies may fit into this landscape.Posadas: The prostate cancer session had a lot of great work in several important areas. One of the big ones [focused on] AR-targeted therapies. We saw updated data with drugs we already know, such as enzalutamide, but we got a nice look at some of the initial clinical data with darolutamide—this information has been anticipated by the field. We also had a nice little taste of what has been happening with PARP inhibitors [in this space]. There is, of course, the immunotherapy question that remains unanswered at this time.

The other nice thing about the prostate cancer updates was that there is a lot of brewing biology. You are seeing it in the form of imaging studies that are being done. For example, PET-imaging studies, which have different conjugates attached to them, such as prostate-specific membrane antigen (PSMA), which has been a hot imaging agent and therapeutic.

Where do you see darolutamide fitting into the treatment paradigm?

Then, there is the idea of looking at different biological phenotypes. We heard a nice discussion about the use of the PAM50 classifier historically being brought into the breast cancer space. The relevance of that general theme is important in prostate cancer and it’s where we will select therapies for patients, including [AR-targeted] drugs as well as PARP inhibitors. We are in for a lot.There are a couple of important things that came out of the ARAMIS trial. First, the bar was set pretty high. With enzalutamide and apalutamide already available and used by most clinicians at this point, darolutamide had to demonstrate that it was just as active [as those agents]. That bar was very clearly met, and I do not think anyone left the presentation hall thinking darolutamide was “a day late and a dollar short” in terms of activity.

Some data that were emphasized were interesting, and a lot of data were actually underemphasized. It was nice that we got to see the chemical structure of the drug, and it became very clear to us that this is a very different molecule—that is important. [It has been] emphasized that it has a lack of penetration into the central nervous system, which will hopefully drive down toxicity; the data seem to support that so far. As more data come in with these larger trials&mdash;TITAN is down the road&mdash;it will be interesting to see how the toxicity matters will play out, especially in a sicker patient population.

Also, because of the molecular structure, the drug-drug interactions are something to consider. This is important because most patients with prostate cancer are older and on other pharmacologics. Having to alter those things can be painful and disturbing sometimes for patients, especially those with complicated medical conditions. The fact that darolutamide has fewer drug-drug interactions is critical.

However, with 3 active compounds now, the question becomes, “Who is on first and who is on second? Is there a role to being on second or third?” The answer is going to speak to the biologic phenotypes. What we know about prostate cancer is that it has the ability to shift in its lineage plasticity phenotype. All these drugs are being used earlier and earlier.

What challenges with enzalutamide and apalutamide led to the rationale of exploring another drug in this space?

We are seeing a trend going back to the LATITUDE and STAMPEDE trials of hitting prostate cancer very hard early in its natural history. This means that with a larger armamentarium of drugs, we have to be judicious about which one we put upfront in order to give us the biggest “bang for our buck,” while also thinking about our strategies for when the patients progress.Enzalutamide has been around for quite a while; it is a drug we love and a drug we do not love for different reasons. It is an extremely potent AR inhibitor; it works, and it suppresses AR signaling very well. Men complain bitterly about the AEs associated with AR inhibition. We are doing what we need to do, but we are paying the price for it. Medical oncologists, and now urologists, are using these drugs but it requires careful follow-up. Enzalutamide has been foundational in our field in that particular sense. When apalutamide came onto the scene, we were very excited to see another agent that was potentially less toxic. However, because of its indications, a lot of payers will only let you have it in the nonmetastatic space.

What are your thoughts on the phase III TITAN trial?

The nonmetastatic CRPC space is getting smaller and smaller by the day. Studying the biology of these 3 agents and personalizing their molecular structure to each patient is going to be very interesting. Our philosophy at Cedars-Sinai Medical Center has always been personalizing care; this is not a one-size-fits-all disease.The TITAN trial should give us different insights as to what the role of these different agents is going to be in terms of metastatic prostate cancer. Because these drugs have been around, and the field is shifting, that is probably going to impact some of the survival data that is associated with the trial. There will be many caveats when the explanations come forward. If the drug is good and really makes a difference, we should see it. However, if the differences are muted, it will be interesting to see what the post-hoc analysis will be.

What are the benefits and limitations of radium-223 dichloride (Xofigo)?

What role will PARP inhibitors have in prostate cancer?

For TITAN, [investigators have] collected some blood and tissue samples to further understand the biology of this disease. This is becoming more vital—understanding what the disease is and what the underlying drivers are.Radium-223 is a wonderful drug for us to have in the field. It is relatively agnostic to the AR; it really utilizes bone biology. This agent has been an important intervention for men with bone metastases. In prostate cancer, it has had a bit of a rocky history due to some toxicity concerns when combined with abiraterone acetate (Zytiga). However, radium-223 has played an important role in bringing awareness to doctors in the area of radiopharmaceuticals. It will remain a mainstay in the field for the treatment of bone metastases, which will always be important in prostate cancer.The PARP inhibitors are a very scientifically interesting class of agents to bring into the prostate cancer space. There is a greater awareness that the homologous recombination deficiency pathways are important in certain subsets of prostate cancer. The use of PARP inhibitors in DNA damage-repair defects is known, but we don’t fully know how to utilize PARP biology in prostate cancer.

Everyone is trying to get them available to patients, and I have had patients with BRCA1/2 mutations who have had remarkable clinical benefit from PARP inhibitors. We, as a field, owe it to our patients to understand the biology of PARP and its relationship with other agents. I am not sure that single-agent PARP is what we need in this space, but when used in combination with other drugs, it could have an impact.

Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 7; abstr 140).