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Nonmetastatic CRPC
How I Manage Patients with Nonmetastatic Castration Resistant Prostate Cancer

Released: June 30, 2020

Expiration: June 29, 2021

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Introduction
I want to start this commentary with 2 of my cases of patients with nonmetastatic castration-resistant prostate (nmCRPC) cancer. I think these 2 cases clearly illustrate how the approval of 3 new drugs—apalutamide, enzalutamide, and darolutamide—in this disease setting have affected the outcomes of patients with nmCRPC.

Case Study 1
The first patient had a radical prostatectomy in 2005 for localized, Gleason score 8 prostate cancer. His prostate-specific antigen (PSA) was undetectable after his surgery, but after 2 years, his PSA rose. He was then treated with local salvage radiation therapy and his PSA went down again. Three years later, in 2010, his PSA rose again and we proposed salvage androgen deprivation therapy (ADT), first administered intermittently and later as a continuous treatment. There was no detectable metastasis on imaging at that time. In mid-2014, his PSA started to rise with a doubling time of less than 6 months. Both bone and CT scans were normal. He was very anxious at this time and enrolled on the randomized phase III PROSPER trial that compared continuous ADT plus enzalutamide vs ADT plus placebo. This patient was in the control arm and for 3 years, which is approximately the time it took for the trial to be completed and to be unblinded, he was very anxious. He was monitoring his PSA independently, and his PSA was rising and rising but with no detectable disease. Off study, he had next-generation imaging with a prostate-specific membrane antigen PET scan that showed an abnormal lymph node in the pelvis; biopsy showed that it was cancerous. Due to progressive disease and the trial unblinding, we were able to treat him with enzalutamide plus ADT and his PSA went down (from 23 in August to 0 the following March) and the lymph node shrank. Today, he is still alive and on therapy.

Case Study 2
The second patient is another man with nmCRPC who was diagnosed with prostate cancer in 1999, with a PSA of 60 and urinary symptoms. He had a pelvic lymph node dissection that was negative and radiation therapy of the prostate, with no ADT at that time. In 2002, his PSA had risen to 15 and then he received intermittent treatment with ADT for almost 10 years. He received continuous ADT starting in 2014, and his PSA stopped rising in 2015, with a value of 0.7 in May 2015. Then his PSA increased to almost 3 in October 2015 and 6 in March 2016, so his PSA doubling time was less than 6 months. His bone and CT scans were normal.

At that time, he enrolled on the phase III ARAMIS trial of continuous ADT with either darolutamide or placebo. This patient received darolutamide and tolerated the treatment well with no detectable adverse events. During the next year, his PSA fell from approximately 9 in April 2016 to almost 0. His bone and CT scans remained normal. Two years after he enrolled on the trial, his PSA began to rise but at a much slower rate compared with before he was receiving darolutamide. Today, he still is doing well on darolutamide with a slowly rising PSA and normal imaging, and his quality of life is excellent. At this time, we are considering doing next-generation imaging and perhaps will consider a local treatment if necessary.

Clinical Trial Summary
These 2 very typical cases illustrate the natural history of nmCRPC before the advent of these 3 new drugs—apalutamide, darolutamide and enzalutamide. Prior to the use of these agents, the time to disease metastasis was typically 1‑2 years, and during this time, patients were extremely anxious since we did not really have any treatment option to offer them.

Now, in all 3 of the randomized phase III trials that evaluated ADT plus either apalutamide, darolutamide, or enzalutamide, the response rate is more than 90% and the time to disease metastasis or death was significantly improved with a reduction in risk of approximately 60% to 70% with a maintained quality of life. Moreover, recent results show that OS is also significantly improved with apalutamide, darolutamide, and enzalutamide. Clearly, giving these drugs to patients with prostate cancer, no detectable metastatic lesions, and a PSA doubling time of ≤ 10 months despite ongoing ADT is effective and should be considered a standard of care.

Choice of Therapy: Considerations for Practice
In clinical practice, choosing which of these 3 agents to recommend for individual patients is difficult because we do not have direct head-to-head comparisons among them. In my practice, I consider the toxicity profiles reported with each agent compared with placebo in the 3 randomized trials along with the individual patient’s clinical presentation to help guide my recommendations. For example, fatigue is approximately twice as frequent with enzalutamide compared with placebo in the PROSPER trial, and approximately one third of patients reported fatigue with enzalutamide and with apalutamide in their phase III trials. In the ARAMIS trial, the incidence of fatigue was 13% with darolutamide vs 8% with placebo.

Some adverse events possibly linked to the CNS penetration of enzalutamide and apalutamide are higher compared with placebo in the PROSPER and SPARTAN trials, respectively. For example, falls were seen in 18% of patients on enzalutamide vs 5% with placebo in the PROSPER trial. For apalutamide, the incidence of falls was 22% vs 10% with placebo in the SPARTAN trial. In the ARAMIS trial, the incidence of falls was similar with darolutamide and placebo (5.2% vs 4.9%). The incidence of bone fractures was also higher with apalutamide (12% vs 7%) or enzalutamide (18% vs 6%) compared with placebo in the respective trials. The incidence of bone fractures with darolutamide was similar to placebo (6% vs 4%) in the ARAMIS trial.

Other adverse events that appear to differ among these 3 agents include an increased risk of hypertension (18% vs 6% with placebo) and adverse cardiovascular events (6% vs 2%) with enzalutamide and an increased risk of rash with apalutamide (24% vs 6% with placebo) that does not seem to be the case with enzalutamide and that seems less common with darolutamide (3% vs 1% with placebo). Hypothyroidism is also reported with apalutamide (8% vs 2% with placebo) but not with the other 2 agents.

Another factor that I consider in my practice is that in the ARAMIS trial, pain progression, which is mostly due to bone metastasis or local progression of prostate cancer, was assessed in a very rigorous way. Therefore, we have direct evidence that darolutamide can prevent pain progression, which is a very good thing for our patients. We currently lack similar rigorous evidence for the prevention of pain progression with apalutamide or enzalutamide.

Monitoring Patients With nmCRPC
Typically, when I start treatment using one of these agents in patients with nmCRPC, I tend to see the patients again after approximately 1 month to make sure they are tolerating treatment well or if a dose reduction is needed—something that is rare with these agents. I also tend to do a first PSA test quite early, at the first visit after 1 month, more for psychological reasons because I know that when my patients see their PSA falling they are much happier. I tend to repeat the PSA testing once every 4 months. Regarding imaging, there are no strong recommendations or strong data. The consensus recommendation from the Advanced Prostate Cancer Consensus conference is to consider doing an imaging once or twice every year, depending on the PSA doubling time. For patients who are responding to treatment, I will probably not image them more often than once per year. However, for patients who do not respond or do not respond well, I would repeat the imaging more often.

To conclude, apalutamide, darolutamide, and enzalutamide all seem to be very active agents in combination with ADT for men with progressive nmCRPC. For the majority of men with nmCRPC and a PSA doubling time of 10 months or less, I am now using one of these 3 agents in my routine practice. However, in those patients with nmCRPC and a PSA doubling time of more than 10 months, at this time, I tend to watch them as we simply do not have evidence that these patients will benefit from these new treatment options.

Your thoughts?
How are you using androgen receptor–targeted agents in your practice for patients with nmCRPC? I encourage you to answer the polling question and join the conversation in the discussion box below.