Gomella Gives Update on Nonmetastatic CRPC Advances

Leonard G. Gomella, MD

The past year has brought therapeutic advancements to the nonmetastatic (M0) castration-resistant prostate cancer (CRPC) paradigm, but more is on the horizon for these patients, according to Leonard G. Gomella, MD.

In February 2018, the FDA approved the first therapy for patients in this setting. Apalutamide (Erleada) was approved for the treatment of patients with M0 CRPC based on findings from the phase III SPARTAN trial, in which the agent plus androgen deprivation therapy (ADT) reduced the risk of metastasis or death by 72%.¹

Following apalutamide, enzalutamide (Xtandi) was approved in July 2018 for the same indication. This approval was based on data from the phase III PROSPER trial, in which enzalutamide plus ADT reduced the risk of metastases or death by 71% compared with ADT alone.²

Looking ahead, the androgen receptor antagonist darolutamide is currently being studied in the phase III ARAMIS trial (NCT02200614) for patients with nonmetastatic CRPC.

Meanwhile, in the metastatic setting, Gomella noted that PARP inhibitors and immunotherapy combinations appear promising,

OncLive: Could you reflect on the approvals of apalutamide and enzalutamide in nonmetastatic CRPC?

In an interview with OncLive, Gomella, professor, chair, Department of Urology, director, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, discussed the shifting landscape of nonmetastastic CRPC, along with other developments across the prostate cancer paradigm. Gomella: The approval of both apalutamide and enzalutamide came in an area that we really had no guidance for before. These were men who had been treated for prostate cancer, but had a slowly rising prostate-specific antigen (PSA) and no evidence of any metastatic disease. Now, having options to treat these patients with 2 agents that interfere with the androgen pathway is very helpful for us. It used to be a watch-and-wait approach for many of these patients until something happened or showed up on a scan. It is great now that we have something that we can use early to reduce the PSA in many of these men and prevent the progression of their disease, or at least delay it for a period of time.

Are there additional studies in this setting that are of particular interest?

In metastatic disease, have we had any updates with PARP inhibitors or immunotherapy in combination with existing agents?

Enzalutamide is a drug that a lot of providers are very familiar with—we have been using it in a different space in more advanced M0 CRPC. There is a lot of comfort using it. However, apalutamide is an equally comfortable drug for a lot of individuals because it is very similar in structure, and in many of the side effect profiles. That decision between enzalutamide and apalutamide really has to do with the individual physician and provider preference. Both have been shown to be effective in 2 large clinical trials in delaying the progression of M0 CRPC. Therefore, a lot of it is really a choice between the comfort level of the provider prescribing the drug.The next drug out there is darolutamide, which is currently in a clinical trial for the same M0 rising PSA but no evidence of metastases population. That drug is probably going to be available in the next 1 to 2 years. It will be a third agent approved in that very defying space. There was not a lot you could do for these patients until earlier this year, when we received approvals for apalutamide and enzalutamide. Darolutamide will be the third drug—more likely than not—to be approved in this space in the next 1 to 2 years.The PARP and immunotherapy stories are very hot right now. We are doing a tremendous amount of basic science research, but also clinical trials of combining these agents together and attacking the cancer in different pathways. We do not have a lot of data yet.

We certainly know that the PARP inhibitors have a lot of activity in men who have very specific genetic alterations in their germline. We believe that one of the PARP inhibitors, olaparib (Lynparza), will be approved shortly, but only in men with metastatic CRPC with a specific series of genetic alterations. It will be a little while until we see the approval for combinations of immunotherapy with PARP inhibitors, but all the early data suggest that it might be the next combination regimen.

How would you categorize the level of personalized medicine in prostate cancer?

In prostate cancer, we are following the lead of many other cancers where 2- or 3-drug combinations may benefit the patient. This is a fairly new area of investigation for prostate cancer. We have been doing it a lot in liquid tumors such as Hodgkin lymphoma, where multiple chemotherapies are used at the same time. We are now actively exploring those areas in prostate cancer.Specifically in prostate cancer, urologists, radiation oncologists, and medical oncologists have been using precision personalized medicine in analyzing the tumor to decide various treatment options, such as active treatment versus active surveillance. We have also been using this genomic testing of the tumor to decide which patients need radiation therapy after radical prostatectomy.

What ongoing research in prostate cancer are you excited about?

The latest area that is really exploding is genomic and genetic testing for inherited prostate cancer risk. We are really far behind breast cancer in this area. The impact of things such as BRCA1/2 in breast cancer is much greater than it is in prostate cancer. However, we are recognizing that these genes are important in prostate cancer, and we are starting to look at them more and more in inherited prostate cancer risk as an approach to personalized medicine.The other area that is getting a lot of attention right now is liquid biopsies—actually identifying individual circulating tumor cells or pulling out individual pieces of tumor-based DNA. Why is that important? The tumor itself is important, but the thing that kills most people is the metastases. Identifying those metastatic lesions and their chemical genetic signature will be very important from both diagnostic and therapeutic standpoints.

The concept of liquid biopsy is very important. Back in the early 1990s, we at Sidney Kimmel Cancer Center did one of the first molecular tests looking for circulating prostate cancer cells. We have a long-standing interest in this and are currently doing other work looking at these circulating factors.

References

1. Small EJ, Saad F, Chowdhury S et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2018;36(suppl 6s; abstr 161).
2. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36(suppl 6s; abstr 3).