Non metastatic CRPC: The Five Essentials - Charles Ryan

Dr. Charles J. Ryan, MD

Charles J. Ryan, MD

Charles J. Ryan, MD is Professor of Clinical Medicine and Urology and the Clinical Program Leader for Genitourinary Medical Oncology at the UCSF Helen Diller Family Comprehensive Cancer Center. He received his MD from the University of Wisconsin in Madison and completed his residency in internal medicine at the University of Wisconsin Hospital and Clinics, where he also served as Chief Resident. He completed a fellowship in medical oncology in the Department of Medicine at Memorial Sloan-Kettering Cancer Center and the Joan and Sanford I. Weill Medical College of Cornell University in New York.

The ASCO Genitourinary Cancers Symposium for 2018 will feature the presentation of two-phase III studies of AR directed therapy in patients with non-metastatic CRPC. Before we get these results we can reflect on why these two studies were done in this patient population in the first place, and what exact clinical need is being addressed by the development of the studies in this space.

The first study is PROSPER : A phase 3, randomized, double blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC).

This study, if positive, would represent a potential new indication for enzalutmaide, which heretofore has received regulatory approval only for metastatic, castration-resistant prostate cancer in the chemotherapy-naive patient as well as in those patients with prior exposure to docetaxel.  It would, in effect, move the use of enzalutamide ‘leftward’ in the clinical states model, to a population with a lower disease burden.

The second study is SPARTAN, a phase 3 double blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). Apalutamide is currently not an FDA approved drug for any indication in the treatment of prostate cancer. Therefore, if positive, this study could shepherd a new drug onto the market.

A key facet of these two trials is what exactly is the question that they are trying to answer and what clinical need is addressed. UroToday will delve into the results of these trials as they become public, and I will not offer any data on this point in this entry. 

To begin, it is unknown exactly how many patients there are with nmCRPC in part because of how this is defined. In order to address some of these questions, as well as the conceptual framework of this clinical state, I present the following five questions for consideration. 

One: Is it actually metastatic disease?

The challenge in diagnosing someone with Non metastatic CRPC is that it is a diagnosis of exclusion. It is impossible, according to logic, to prove the absence of something. So the implication with non-metastatic is that you looked for metastases, but you didn’t find them. What does that really mean – you looked? In a study that I led with Abiraterone, the Imaagen study, we found that about 35% of patients who we screened for the study because we thought they had non-metastatic disease actually had metastases; they just hadn’t been scanned in the last 6 months! So keep in mind that proving ‘in’ non-mets requires some diligence in ruling ‘out’ metastases. 

So actually doing scans is one thing, which scan to get is another. 

The studies relied on standard imaging- CT and Bone scan. But the times are changing. The proliferation of Axumin® (fluciclovine F 18) and PSMA PET scans means that we are finding more occult metastases. I have, on several occasions, found nodes and other findings on PSMA PET/MRI scans, which we do here at UCSF on a research basis, in patients who have completely negative CT scans and bone scans. So if the new imaging procedures proliferate, as they are expected to, we may find that the pool of patients with ‘non-metastatic’ CRPC will shrink.

And from a therapy perspective, we need to study and continue to think about what clinical difference there is between a patient with 1-3 ‘oligo’ mets found on PSMA PET and someone who has actual metastases showing up on a regular CT and bone scan. 

In my practice I have treated a few patients who have 1-2 distant mets on standard scans with focal therapy, and there is an emerging body of thought and literature on radiation of such lesions detected on PSMA PET. My own bias is that there probably are some patients out there with oligometastatic disease who can achieve long-term benefit from the focal therapy of oligomets, but I am only hypothesizing. We need a study to do that. 

One potential study design would be to randomize patients with oligometastatic disease to SBRT to the lesions VS AR directed therapy. Another would be to treat all patients with AR directed therapy, and randomize patients to receive radiation or not.

Two: How did the patient get there?

Some patients start out with metastatic disease but respond so well to initial ADT that the metastases disappear. This is especially common with pelvic nodes. They may subsequently go on to develop CRPC. They have nmCRPC

Other patients have had a radical prostatectomy with our without salvage RT, and then go on ADT for a rising PSA only and later go on to develop CRPC. They have nmCRPC

Still other patients may not have the prostate removed and may have locally advanced disease (in the prostate) after undergoing primary ADT or ADT with radiation, and then go on to develop CRPC. They have nmCRPC.

These clinical entities are probably different, but we’re not really sure how actually different they are.

Three: What is the PSA DT?

As one might imagine, the prognosis of patients without metastasis is highly variable. Also, because this is “PSA Only” disease we really have only one parameter to follow, so the prediction of outcome in such patients can only really be done through PSA kinetics. In a pivotal study years ago that explored the use of zoledronic acid in preventing metastatic spread (it didn’t) Matthew Smith of Massachusetts General Hospital Cancer Center described a curious phenomenon related to PSADT (PSA doubling time) and development of mets: a severe inflection point at around 9 months. A PSADT > 9 months was associated with a low risk of metastatic disease, whereas the risk shot up asymptotically as with progressively faster PSADT. Since this is, by definition, “PSA only” disease, it is absolutely critical to know the patients PSA doubling time, as this is the principal disease-defining characteristic.

Four: Is local (prostate directed) therapy an option?

Some patients who received ADT for local therapy only (I believe there are few anymore) may in fact harbor the bulk of their disease in the prostate only. In particular, in the case of a patient with lower urinary tract symptoms, consideration may be given to administering local therapy (likely EBRT) in lieu of systemic therapy. Quite possibly both will be needed -that’s a research question.

Five: Is doing nothing a reasonable option?

I have patients with metastatic CRPC who harbor indolent disease, and while I am generally an advocate for early, proactive intervention, I believe that some patients will do equally well if such intervention is delayed for a few months. There is no ‘doing nothing’ in these cases, because you do need to follow them closely. In addition to PSA’s, they may need regular scans and other potential markers of a growing disease burden such as the alkaline phosphatase, LDH etc. but until someone shows me that there is a significant difference in outcome in a patient who starts therapy at a PSA of 2.5 vs. 5.0, which may be three months later, I might wait that three months in some patients and avoid the cost and toxicity. Again, another research question.


Written by: Charles Ryan, MD 

References: 

Smith MR1, Kabbinavar F, Saad F, Hussain A, Gittelman MC, Bilhartz DL, Wynne C, Murray R, Zinner NR, Schulman C, Linnartz R, Zheng M, Goessl C, Hei YJ, Small EJ, Cook R, Higano CS. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005 May 1;23(13):2918-25
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