Personalized Medicine Is Next Step in Castration-Resistant Prostate Cancer

Raoul S. Concepcion, MD, FACS

The field of castration-resistant prostate cancer (CRPC) is moving forward with the development of several new treatment options, and the next steps for clinicians will be tailoring treatment strategies to each individual patient, said Raoul S. Concepcion, MD, FACS.

The phase III ARAMIS trial introduced a third androgen receptor inhibitor that may shake up the treatment paradigm for patients with nonmetastatic CRPC. In this study, the addition of darolutamide to androgen deprivation therapy (ADT) was found to significantly improve metastasis-free survival (MFS) versus ADT alone, with comparable tolerability to enzalutamide (Xtandi) and apalutamide (Erleada).

The findings, which were presented at the 2019 Genitourinary Cancers Symposium, showed the median MFS was 40.4 months for patients treated with darolutamide compared with 18.4 months in those who received ADT alone (HR, 0.41; 95% CI, 0.34-0.50; P <.0001). At a median follow-up of 17.9 months, the median time to pain progression also favored darolutamide at 40.3 months compared with 25.4 months with placebo, which translated to a 35% risk reduction (HR, 0.65; 95% CI, 0.53-0.79; P <.0001).

Although additional data will be critical in determining where darolutamide will fit into the nonmetastatic CRPC space, Concepcion, director of the Comprehensive Prostate Center, and clinical associate professor of urology, Vanderbilt University School of Medicine, said that cost could be the biggest deciding factor.

Beyond this approach, immunotherapy in the form of PD-1/L1 inhibitors could soon have a more significant role in the treatment of patients with metastatic disease, Concepcion predicts. As the space continues to move away from traditional approaches, the ability to interpret and utilize predictive biomarkers will become all the more important, as they will help inform which treatment will result in the greatest clinical benefit.

OncLive: How has the results from the ARAMIS trial impacted the nonmetastatic CRPC landscape?

In an interview with OncLive, Concepcion, who is also the editor-in-chief of Urologists in Cancer Care, discussed the clinical implications of the findings from the ARAMIS trial and highlighted other therapies that are coming down the pike for the treatment of patients with CRPC.Concepcion: ARAMIS was a highly anticipated trial mostly because the drug itself, darolutamide, is structurally different than apalutamide and enzalutamide. In this trial, investigators were looking at patients with nonmetastatic CRPC, a very similar population to [those evaluated] in the SPARTAN and PROSPER trials. In other words, these patients had a diagnosis of prostate cancer, were on ADT, had testosterone levels in the castration range, and had rising prostate-specific antigen (PSA). They were imaged and showed no evidence of metastatic disease by traditional imaging, which includes a bone scan and a computerized tomography scan. Enzalutamide and apalutamide are FDA approved for these patients. The inclusion criteria for these patients was to have a PSA doubling time <10 months, when in reality, this patient population has a doubling time less <3 months.

The theory of darolutamide being structurally different is that there may, in fact, be less toxicity relative to central nervous system (CNS) adverse events. What they reported out [at the 2019 Genitourinary Cancers Symposium] was what many people anticipated: the time to metastases was delayed versus placebo. But what would be the side effect profile? This [question] was specific to fatigue, because enzalutamide and apalutamide have a very significant fatigue factor somewhere in the order of 20% to 30%. What they reported at the symposium was that in the darolutamide arm, the incidence of fatigue was approximately 15%; in the placebo arm, it was 12%. Therefore, there is definitely a reduction in the incidence of fatigue. Again, the delay to MFS was pretty much similar to what we saw with enzalutamide and apalutamide in this nonmetastatic CRPC population.

Where do you see darolutamide fitting in this treatment paradigm?

What is the importance of evaluating quality of life (QoL) in clinical trials?

What does the future hold for immunotherapy in prostate cancer?

These data are significant, and there will be more data coming out on this. [The questions of] how this is going to translate into practice and how we are going to use darolutamide versus the other 2 agents still need to be flushed out. Cost will be a big factor, and it will be interesting to see how long it will take for an approval.This is going to be an interesting question. Now, we have potentially 3 agents that have been studied with positive trials in this setting. The challenge for clinicians is going to be: which drug do we use? For urologists in particular, our experience with enzalutamide going back to 2012 means that we are very comfortable with using it. Because apalutamide has recently been approved [by the FDA] and it is a very similar product, the urology world is getting used to this. With darolutamide, once investigators start looking at the side effect profile, what is going to be the willingness for the provider to use this drug? It will probably be related to how they view individual patients. If you have a patient who already has a lot of central nervous system toxicity and fatigue, darolutamide may be a more preferable option. However, like anything else, when you look at the primary endpoints, these drugs are very similar in their results. It may ultimately just come down to cost.We know there are so many agents that prolong survival. What many people do not realize is that in many of these patients with CRPC—especially if they are nonmetastatic—their ECOG performance status is 0; they are highly functional and active. These are not patients who are walking around in significant pain. The issue with some of these agents is that their side effect profiles may set these patients back. If therapy is going to slow down what patients are able to do on a daily basis, that becomes significant. I'm glad we are emphasizing QoL into the equation here. It is happening across the board with all of these targeted therapies, and it should become the standard in clinical trials moving forward.Over the years, the utilization of ipilimumab (Yervoy) had minimal efficacy in CRPC. However, we know that mCRPC tumors are “cold” tumors—they are not that immunogenic. There are a lot of data now, especially in men with mCRPC who have moved through several lines of therapy, where we do see this mutational burden. There are [biomarkers] that come as a result of treatment pressure selection. The 2 that come to mind are microsatellite instability (MSI) and CDK12. If you take these 2 groups, a percentage of patients will actually respond to a PD-1/PD-L1 inhibitor. Therefore, there is going to be a place for our newer immunotherapies, but what [this will depend on] is the clinicians understanding which testing they need to order.

What are biggest challenges moving forward?

As we move from our traditional therapies, the ability to interpret these predictive markers becomes really important. Testing for MSI and CDK12 biallelic loss with anticipation that we will also see [FDA] approvals for PARP inhibitors—understanding where these factors lie, how to process the results, and make them actionable is crucial. The challenge is going to be utilizing these biomarkers and next-generation imaging.If we start from initiation of disease, for newly diagnosed prostate cancer, the question is going to be, “How can we determine who most needs treatment? Who needs active surveillance?” Urologists are looking at that appropriately. We are even taking that one step further in asking who we need to biopsy. Just because a patient's PSA is elevated doesn't necessarily mean that they need to undergo a biopsy. We are [working on developing] a better understanding of how to utilize PSA in conjunction with some of this adjuvant testing—whether it be blood-based, urine-based, or now, imaging-based with magnetic resonance imaging.

With definitive therapy, some of the challenges are in patients with high-grade prostate cancer who we know are going to progress. Who are the patients who will benefit from adjuvant radiotherapy? We also know there are ongoing trials in patients who have been definitively treated and have a biochemical recurrence. We know these patients are at a higher risk of developing metastatic disease. The EMBARK trial is looking at these patients and giving them ADT alone, enzalutamide alone, or the 2 modalities combined; that will be a significant trial. Getting back to localized prostate cancer, we know that there is a trial looking at sipuleucel-T (Provenge) in patients who are candidates for active surveillance.

The point here is, for the practicing urologists, to really look at prostate cancer and try to isolate patients into these individual buckets. It does become a mastery of the clinical trials and the particular phenotype we are dealing with, as well as the drugs that are approved [by the FDA] or not. There is no doubt it is becoming complex. We are going to see more agents, and we can guess that immunotherapy will play a bigger role. We know some other mechanistic drugs will come to the table. For urologists, it used to be operating, putting the patient on ADT, then seeing what happens. Now, we have to critically look at these patients.

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 7S, abstr 140). meetinglibrary.asco.org/record/170190/abstract.