Ralph V. Boccia, MD

 Today a couple of the more exciting drug classes include the PARP inhibitors. We would be looking at BRCA and other mismatch repair pathways where we might be able to use a PARP inhibitor because some of them are extraordinarily effective. The other is to see whether the patient might have microsatellite instability, might have PD-L1, PD-1 overexpression, so that we could use PD-L1 or PD-1 drugs. The immuno-oncology drugs—we’re now using some of them in up-front studies. Clinical trials are critically important for us to be able to accrue our patients to looking at all the new targets that we have in oncology in general and prostate cancer, urologic oncology specifically.

From a community standpoint, we’re on the front lines. We’re seeing more patients than they are in academic centers. We’re faced with the day-to-day discussions with our patients, finding effective therapies, hopefully preserving quality of life and improving quantity of life. With a patient with metastatic castration-sensitive disease, it’s important to prolong this progression-free survival as long as we can, and that’s progression from PSA [prostate-specific antigen] rise, progression from radiographic progression, progression from organ involvement and preserving quality of life. We still will forever always be using androgen deprivation therapy as a cornerstone and then picking from there what we consider the most effective drugs.

Looking at the drugs, we have several, as I’ve already mentioned. Now that we have options to move our patients onto androgen deprivation therapy. Now it’s critically important to look at the adverse-effect profiles. They are disparate enough that picking the drugs is very important. The 1 I tend to talk to my patients about most, and the 1 that sticks at the back of my mind because of my experience using the drugs that are on the market now, is the fatigue. The fatigue with the class of drugs we’re using today, the androgen receptor blockade, is probably the 1 where it can be the most prominent. What I find is that apalutamide tends to have significantly less fatigue than, for instance, enzalutamide.

My go-to drug has been apalutamide over enzalutamide for that reason. We’re sequencing patients as best we can. We’re looking at genomics as early as we can. We’re starting patients on the best-available therapies as early as we can because preventing progression is preventing resistance, and that’s the reason that progression can be prolonged. When you tend to use drugs with different mechanisms of action—ie, androgen deprivation therapy on the 1 hand and androgen blockade on the other hand—you tend to reduce that chance of developing resistance and improving these patients. You’ve got to look at quality of life when you’re doing all this, because if you administer a drug to any patient with any malignancy and they’re debilitated by it, you haven’t done them any service.

Case: A 66-Year-Old Male with Metastatic Castrate-Sensitive Prostate Cancer

A 66-year-old man presented with mild intermitted back pain

PMH: DM; medically controlled; OTC analgesics for pain

PE: DRE revealed an enlarged prostate; otherwise unremarkable



Core needle biopsy with TRUS showed adenocarcinoma of prostate

Bone scan revealed 4 spinal lesions (T8/T9, L1/L2) and 1 in the right femur

Chest/abdominal/pelvic CT scan was negative for distant metastases

He was started on ADT + apalutimide 240 mg qDay

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mCSPC: Incorporating Newer Therapies Into Practice

 We might ask ourselves: Why might multimodality therapy work in a patient with castration-sensitive metastatic prostate cancer? Why would you choose an androgen receptor inhibitor as opposed to something else? We’ve known for many years that prostate cancers in general are driven by the male hormone, androgen testosterone. But what happens at the level of the prostate, especially when resistance develops, is that there is constitutive or constant activation of the androgen receptor in the gland that drives the cancer, no longer requiring testosterone. You’re always going to have testosterone or castration-sensitive cells even later, which is why we continue androgen deprivation therapy even when they become the so-called castration resistance. But that combination of blockade at the prostate level will enhance that activity, which is why we see in TITAN that the results with apalutamide are so much better than with placebo and why the patients might go longer before they develop resistance.

When we follow patients, we have a set pattern for how we follow them. PSA [prostate-specific antigen] has typically been the best measure of how therapies are working in the easiest fashion. You can get a PSA anytime. It isn’t expensive, and typically if patients’ PSAs are elevated and go down, that generally means a response. If they’re lower or whatever level that they go up to, that typically means the patient is progressing.

The progression of PSA does not mean you can measure it any other way. You can’t always measure it radiographically, but it typically means that something is probably happening. Most of us would measure PSAs on some interval basis. It might be measured monthly for a couple of months until you’re sure the patient is responding, and then after that it could be every 3 months. It might be even longer than that, but most of us would probably measure it no less often than every 3 months. If the PSA rises, it’s certainly time to look for radiographic progression, look for the development of new metastases, because that would always indicate that the patient has developed potentially castration resistance.

That said, I want to add 1 caveat to that. Like a lot of tumors, as tumors progress, they often develop multiple mechanisms by which they become resistant. Sometimes the genomics change to the point that, in this case, PSA rise isn’t always measurable. Patients’ tumors may dedifferentiate, and they may no longer produce PSA to the same degree. If a patient develops new symptoms, that’s also a time to be looking for radiographic progression because the PSA isn’t always that perfect indicator.

Anytime you’re faced with progression of cancers in general, typically we always look for a drug that may have a different mechanism of action, presuming that resistance is going to cross over to another drug that happens to have the same mechanism of action. That is why when we had patients in the old days on abiraterone or enzalutamide, although we didn’t have other good options to move to then, chemotherapy was always an option. In a patient who has slowly progressing disease, who you no longer think is responding to the drug you’re using, sometimes we’ll look to use that other drug. We would do that in the old days, but responses are very low, on the order of maybe 10% at best. We really would be looking for a drug with a different mechanism of action.

Today we’re certainly in the targeted drug genomic era. We would be looking at whether we could find another target that we could go after other than the androgen receptor. Earlier on, we would get genomic profiling of the tumor and send off next-generation sequencing, looking for things such as microsatellite instability, DNA repair, and mismatch repair so we could use things like some of the immuno-oncology drugs and some of the PARP inhibitor drugs. But looking for a different mechanism of action should be looked at as soon as you have progression of disease because you may find a unique target where you could find a uniquely specific and effective therapy.

AR-Targeted Therapy for mCSPC: Monitoring for Progression

 Adverse events are part of any therapy that we use in oncology, and they certainly occur within androgen deprivation therapy and with apalutamide. Remember, TITAN is a randomized placebo-controlled trial, so it’s easy for us to compare what additional toxicity apalutamide might add to androgen deprivation therapy. There were several of them, some of which are unique. Fatigue can certainly occur. About a quarter of the patients had some degree of fatigue, but only on the order of 6% or 7% of the patients had a grade 3 or 4 fatigue. Fatigue can occur but tends to be relatively low grade. In addition, there were some unique things like skin rash. About 28% of patients developed a skin rash, which tends to occur relatively late. You’ve got to watch out for it during their continued course, on average a couple of months after initiating therapy. About 5%, 6%, or 7% of the patients can get a grade 3 or 4. It is something to watch for, something you may need to reduce for.

Falls and fractures. Remember, this tends to be an older population of patients, they may not have quite the same steadiness in their later years that they had in their earlier years, so falls can occur. If you fall, you can have a fracture. Could it have something to do with cognition? We’re not quite sure. But about 12% of the patients have falls in the apalutamide arm compared with about 7% of the patients in the placebo arm; it does occur with a higher rate. Same with the fractures—higher risk of falls, higher risk of fractures. None of them is very numerous, but they are nonetheless definitely significant.

And then seizures. We saw a few patients develop seizures in this trial. On the apalutamide, it was 0.4%, and on the placebo arm it was 0.1%. Seizures don’t occur with any frequency of either arm but certainly can occur with a higher frequency in patients on apalutamide. For that reason, it might not be the right drug for a patient who has epilepsy.

AR-Targeted Therapy for mCSPC: Adverse Events

 The phase 3 TITAN trial was conducted in men with castration-sensitive metastatic prostate cancer. Patients who were randomized to receive the old standard of care, which was androgen deprivation therapy [ADT], vs the experimental arm, which was androgen deprivation therapy plus apalutamide. This was a randomized double-blind trial. It was androgen deprivation therapy plus apalutamide vs androgen deprivation therapy plus placebo—a placebo-controlled trial.

Men were risk stratified based on their volume of disease, whether they had had prior therapy and whether they had received prior chemotherapy with docetaxel. Patients were then given either androgen deprivation therapy plus placebo or androgen deprivation therapy plus apalutamide, 240 mg once a day, which is the approved dosage that we use in clinic today. Patients were then monitored with radiographic scans and PSA [prostate-specific antigen].

The coprimary end points were overall survival and radiographic progression-free survival, to see how long patients went with therapy and no progression of their scans, whether bone or CT scans. The secondary end point was the time to needing chemotherapy—how long could patients be treated with endocrine therapy alone before they progressed, became castrate resistant, and required cytotoxic chemotherapy. Those were the end points we used in that clinical trial to determine efficacy and see whether this drug was worth introducing into clinic via the FDA-approval mechanism.

Responses were seen both in the primary end points as well as the secondary end points. This trial met its primary and secondary end points for overall survival. The risk of death was decreased by 33% in the patients treated with apalutamide plus ADT vs those patients treated with placebo plus ADT. That’s a hazard ratio of 0.67, a 33% reduction in the risk of death. The other coprimary end point was the radiographic progression-free survival, and this delayed by 51% progression on x-rays. Of those coprimary end points, it also met—as I just mentioned—its secondary end point, which was time to requiring chemotherapy. There was a 61% reduction in the risk of needing chemotherapy on the apalutamide-plus-ADT arm compared with the placebo-plus-ADT arm. It met all 3 of its primary and secondary end points.

Based on the data you just heard, the prognosis of patients with high-volume disease, most all of us would recommend that as soon as metastatic castration-sensitive disease is diagnosed, the patient ought to be put on combination therapy with apalutamide and androgen deprivation therapy, certainly supported by the TITAN trial or at least considered for it.

The TITAN Trial in mCSPC

 We always have to consider all the potential comorbidities that patients have when we try to target the specific therapy that would be best for them. With abiraterone, as I mentioned to you, you must use an additional steroid, hydrocortisone. When you use androgen blockade, you can potentially decrease corticosteroid synthesis, and you have the potential to cause adrenal crisis in those patients. We always give additional corticosteroids in patients now who are given abiraterone. The patient who we’re talking about has diabetes, so anytime we give a corticosteroid to a diabetic patient, the gluconeogenesis that occurs can often cause havoc with controlling the patient’s blood sugar. This would not be the best patient to go ahead and give abiraterone to with his androgen deprivation therapy. I’d much rather give either enzalutamide or apalutamide rather than abiraterone.

We like to risk stratify our patients with almost any disease. Whether we’re using monotherapies or multiagent chemotherapies, they’re often going to be defined by what our goal is for that particular patient, the volume of disease they have, and the outcomes and goals we’re looking for, just as we talked about earlier. This is a man with high-volume disease. If we use single-agent monotherapy with androgen deprivation therapy, I quoted you the data, this patient has a short progression-free survival, and then we’ll be on to other things anyway. We want to look at the data for the other clinical trials and see whether we can get around some of those short progression-free survival and potential overall survival issues that we’ve already talked about.

mCSPC: Patient Variables and Treatment Selection

 When faced with a patient such as this, we must ask ourselves, “What would our treatment goals be?” Obviously, everyone thinks about survival, so 1 of our goals would be to prolong this man’s life as much as possible. Remember, this man already presents with symptoms from his bony metastatic disease, so another goal would obviously be to control his pain. We want to be able to offer him a therapy that’s tolerable, so we can provide him quality of life. Quality of life, control of symptoms, improvement in survival as best we can.

Our next step talking with this man is going to be what kind of therapy can we offer him. Any time we sit before a patient with any type of cancer, we want to be able to offer them options. The options as we describe them must be data based. We have to be able to offer them evidence-based results so they can help us choose what’s best for them. We take into consideration comorbidities, age, and variety of social factors. All those must come into play. But if you look just at the NCCN Guidelines for a patient such as this without taking into account those other peripheral issues, you see a number of things that are recommended.

In the not-too-distant past, for many years, single-agent monotherapy androgen deprivation therapy was considered the appropriate approach for a patient with castration-sensitive disease. What used to be category 1 is now deescalated to a category 2A, and the reason is we have alternative endocrine or targeted therapies that will improve progression-free and overall survival significantly.

Those would include the old therapies, such as abiraterone with androgen deprivation therapy. Let me give a caveat by saying that androgen deprivation therapy is still and always will be the cornerstone with which we continue to treat patients at all stages of the disease, whether they’re castration sensitive or castration resistant. We then add to that other potential agents to build on the efficacy, response rates, quality of life, and build on the survival. Androgen deprivation therapy is still considered an option for patients but no longer a category 1; it’s a category 2A.

Then we have 1 of the first drugs, abiraterone, that we can block. In fact, the conversion to testosterone in the adrenal glands and further improves the control of the cancers in combination with androgen deprivation therapy. That’s an old drug and has its own issues regard to other steroid therapies and requirement of steroid replacement therapies. We have newer drugs that are more targeted to the androgen receptor: enzalutamide, abiraterone, and apalutamide. We have those in combination with androgen deprivation therapy as options.

What you’ve got to do when you talk about androgen deprivation therapy plus androgen receptor–targeted therapy with either enzalutamide or apalutamide is the potential off-target toxicities or adverse events that these can cause. We have androgen deprivation therapy, androgen deprivation therapy plus abiraterone, androgen deprivation therapy plus apalutamide, androgen deprivation therapy plus even a taxane. Docetaxel, which we’ve used for many years in patients and became castration resistant before some of these targeting agents became available, is also considered to be a reasonable agent based on STAMPEDE and other trials, even in the frontline setting. That’s an option for patients. Clinical trials are always an option, and we have some other androgen-targeted therapies that we can use as well.

Ralph V. Boccia, MD | Authors

Articles

mCSPC: Incorporating Newer Therapies Into Practice

AR-Targeted Therapy for mCSPC: Monitoring for Progression

AR-Targeted Therapy for mCSPC: Adverse Events

The TITAN Trial in mCSPC

mCSPC: Patient Variables and Treatment Selection

Frontline Therapy for mCSPC