Advancements Emerging in Nonmetastatic and mCRPC Paradigms

Tanya Dorff, MD

Two critical clinical trials—SPARTAN and PROSPER—served as the basis for the 2018 FDA approvals of apalutamide (Erleada) and enzalutamide (Xtandi), respectively, agents that have drastically changed the standard of care for patients with nonmetastatic castration-resistant prostate cancer (CRPC), said Tanya B. Dorff, MD.

During the 2018 OncLive^® State of the Science Summit^TM on Genitourinary Cancers, Dorff explained that these approvals have established a foundation for subsequent progress for patients with nonmetastatic CRPC.

In the metastatic castration-resistant prostate cancer (mCRPC) space, more research is moving forward with immunotherapy, PARP inhibitors, and imaging techniques.

“As we define molecular subsets, and we find the drugs that have a big impact, such as PARP inhibitors in patients with DNA repair deficiency, it will likely be amplified in earlier [lines of therapy]. It’s what we’ve seen with docetaxel in CHAARTED and abiraterone acetate (Zytiga) and docetaxel in STAMPEDE and LATITUDE,” said Dorff. “The earlier we use these drugs, the better. The big space to focus on is trying to bring more durable responses to patients, provided we don't do it at the cost of quality of life (QoL).”

OncLive^®: What trials have defined the field of nonmetastatic CRPC?

In an interview with OncLive^® during the meeting, Dorff, associate clinical professor in the Department of Medical Oncology and Therapeutics Research, and head of the genitourinary cancers program at City of Hope, discussed landmark approvals in nonmetastatic CRPC and anticipated developments in metastatic CRPC.Dorff: For nonmetastatic CRPC, there were 2 landmark studies that have now changed the way we practice. First and foremost, it's important to image patients whose prostate-specific antigen (PSA) is rising despite castration therapy, so that we can correctly categorize them as metastatic or nonmetastatic—–even oligometastatic versus large-volume metastatic disease. When we do find patients who are truly nonmetastatic castration-resistant, but we can't find anything on conventional imaging, we need to check their doubling time to categorize them as high-risk or not. We use a PSA doubling time cutoff of £10 months. That's what was used in both of the trials.

If a patient meets all those criteria, we now have treatment options for them, whereas before we really didn't. We used to do some secondary hormonal manipulations, but there was nothing we knew would improve survival. Both apalutamide and enzalutamide were studied in large randomized trials and showed a positive primary endpoint of metastasis-free survival (MFS). This is a new endpoint for the prostate cancer community, but it led to the FDA approval of these drugs in this context. It’s clinically meaningful and resonates with patients.

We don’t have comparative data between apalutamide and enzalutamide. Either one is a perfectly acceptable option. There are some slight differences between their side effect profiles, but generally speaking there is no major reason to choose one or the other.

Do payers have a preference with regard to apalutamide and enzalutamide?

Additionally, QoL seems to be maintained on these drugs. The other major thing to emphasize is that fractures were seen on one of the studies. These men have been castrated for quite a while and are going to continue on castration therapy, so we have to pay attention to bone supportive therapy when we're treating men in this earlier-disease setting.It's possible that insurers may have a preference. I did have that situation with one patient. [A payer may opt for one drug] if it is priced more favorably for their group. Falls or seizures are side effects we traditionally associate with enzalutamide. If a patient has had issues with falls or seizures, one might think we should choose apalutamide.

How important is supplementing treatment with bone-supporting agents?

Looking to the future, what's coming down the pike?

However, the side effect profile overlaps there. There are no patient characteristics that stand out, and there shouldn't be a patient preference, I would think. It would be rare to find a patient who had been exposed to both and could tell you about both of them. It's going to be up to doctors to get a feel for the drugs and see how they work relative to each other in this population.Bone health is becoming increasingly important as we hear about studies like ERA-223 with increased fractures. As we move into this earlier disease state, in which men are going to be on therapy for a lot longer, we can use bisphosphonates, such as alendronate. We can use 5 mg of zoledronic acid once yearly, or 60 mg of denosumab (Xgeva) every 6 months. All patients should be instructed to take calcium and vitamin D. Weight-bearing exercise is also likely important to help maintain bone strength. It's something that we need to pay attention to. What is coming in this space is imaging. A lot of people believe that as we get more sensitive PET scans, we will no longer categorize patients as having nonmetastatic CRPC. We know the cancer cells are there, so it's semantics. We know they're metastatic. It's just a question of whether they're micrometastatic or macrometastatic on imaging.

You also spoke on metastatic CRPC. How should clinicians approach sequencing in that space?

As Gallium-68 prostate-specific membrane antigen (PSMA) and other PSMA agents become available, this population will shrink. Metastatic hormone-sensitive will become the new frontier to try new agents in upfront intensification. Of course, genomic characterization is the other big paradigm shift that should be brought into the mainstream once we have approval of agents that are designed for specific molecular subclasses.When we’re sequencing for metastatic CRPC, we have a whole host of options now, which is great. I remember when I started practicing, I just had standard castration, a couple of androgen receptor drugs, such as bicalutamide (Casodex), and chemotherapy. Now, we have all these choices that have been proven to prolong survival, maintain a good QoL, and reduce skeletal symptomatic events. It becomes an opportunity to individualize treatment in the absence of directly comparative data. There is no one right sequence.

You may have a patient who you might want to give chemotherapy to after they’ve received abiraterone or enzalutamide. However, they might be elderly, or they might be young and working and can't afford to quit their job for the 6 months that you want to give them chemotherapy. We have radium-223 dichloride (Xofigo), which is a nice option for patients who have bone-only or metastatic disease that is limited to the bone. For patients with soft tissue and visceral metastases, that's not an option. On top of chemotherapy, abiraterone, and enzalutamide, there is immunotherapy with sipuleucel-T (Provenge) for select patients. Those patients should be minimally symptomatic, asymptomatic, and have slowly progressing disease.

What is the future of PARP inhibitors in this space?

It's important to look at the patient's characteristics and think through the pace of their progression. Moreover, what is the distribution? Imaging becomes key in this context as well. Sometimes PSA can be going up, even though the patient looks and feels great. We really want to get the most mileage out of treatment. If their scans aren’t changing, it’s probably not appropriate to switch therapy.PARP inhibitors will be the next drugs approved for prostate cancer, and I think it will happen in 2019. There are phase III trials that have completed showing that these drugs are effective in BRCA-mutated and certain other DNA-repair deficiency populations.

Where would you like to see researched focused moving forward?

We're going to see comparative studies of olaparib (Lynparza) versus physician's choice of abiraterone, enzalutamide, or docetaxel. Those studies are going to be important in benchmarking. It will be the first sort of directly comparative data we'll have about some of our existing strategies and new strategies. This will make a huge impact. Unfortunately, it's only 20% or 25% of patients who have the right mutation. For those patients, it's going to be a very nice additional tool. [I would like to see it focused] in the metastatic hormone-sensitive or perhaps biochemical recurrence settings. Additionally, a lot of newer studies incorporate patient-reported outcomes. That’s important. Since this is a longer-term disease process, we want men to live well as they're living longer.

The other space that's open for revolution is immunotherapy. It's been disappointing that the immune checkpoint inhibitors haven't been as successful in these patients. Sipuleucel-T (Provenge) has been around a while; we know men live longer when they get it. We're looking for something that will be game-changing. There are many studies that are combining radiation with immunotherapy, immunotherapy plus immunotherapy, and exploring which hormone therapies are most immunogenic. It will take a little bit longer for that to make its way into clinical treatment, but it's definitely on the horizon within the next 5 years.