Apalutamide Approval Paves Way for Further Advances in Nonmetastatic CRPC

Alan H. Bryce, MD

Alan H. Bryce, MD

The space of nonmetastatic castration-resistant prostate cancer (CRPC) is beginning to evolve with recent advances highlighted by the FDA-approval of apalutamide (Erleada).

The FDA based its decision on findings from the phase III SPARTAN trial, in which the median metastasis-free survival (MFS) was 40.5 months in the apalutamide arm versus 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; P <.0001).¹

Similarly, in the phase III PROSPER trial, the combination of enzalutamide (Xtandi) and androgen-deprivation therapy (ADT) led to a median MFS of 36.6 months versus 14.7 months with ADT alone in patients with nonmetastatic CRPC.²

Darolutamide, an androgen receptor antagonist, is also under investigation in M0 CRPC. The study has not yet been announced, but the community is anticipating seeing data by the end of 2018, according to Alan H. Bryce, MD.

“Potentially, we'll have 3 new FDA-approved treatment options in what was previously an orphan space,” Bryce said.

OncLive: What recent developments have there been in nonmetastatic prostate cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Bryce, assistant professor of medicine, Mayo Clinic, discussed emerging agents and next steps in the treatment of patients with in nonmetastatic prostate cancer.Bryce: We now have the first FDA-approved drug for treatment in nonmetastatic prostate cancer. This is a result of 2 exciting studies we saw at the 2018 Genitourinary Cancers Symposium in February. The approved drug, apalutamide, demonstrated a progression-free survival advantage in the setting of castration-resistant nonmetastatic disease. This was in patients with biochemical recurrence who no longer responded to leuprolide acetate (Lupron). We know these patients have a fairly short interval to the development of metastatic disease, at which point they have a life expectancy of 3 to 5 years. The prevention of metastatic disease is the key to try to prevent morbidity, progressive disease, and mortality.

How will the integration of these treatments potentially affect the use of chemotherapy in nonmetastatic prostate cancer?

The PARP inhibitor olaparib (Lynparza) has shown promise in mCRPC. Are there other settings in which PARP inhibitors have potential?

Apalutamide is a next-generation antiandrogen. The most prominent side effect appears to be rash. It's very well tolerated by patients and easy to take as a daily pill. Also presented at the 2018 Genitourinary Cancers Symposium was the enzalutamide study. The results showed that it delays the time until development of overt metastases when compared with placebo.One of the endpoints we see in nonmetastatic clinical trials is the time until the use of chemotherapy. Patients feel it is a clinically meaningful endpoint if we can do anything that delays the use of chemotherapy, which is generally more toxic and has a more dramatic impact on quality of life. Ultimately, chemotherapy still has a role to play in prostate cancer, and it's really the oncologists’ main task to figure out how to deploy each drug in the armamentarium in its optimal space. Nevertheless, it's an attractive narrative that we are delaying the time until patients need what is conceptually a scarier treatment option for them. PARP inhibitors are definitely a major advancement that are being explored in prostate cancer. We've come to understand that 8% to 12% of all patients with prostate cancer have defects in DNA-repair pathways, specifically BRCA1/2, ATM, and a longer list of less common abnormalities. Many of these defects are going to be susceptible to PARP inhibition, and that's just taking into account patients who have germline risk. In somatic mutations, the rate of those abnormalities jumps to 25% to 30%. This is already FDA approved in breast and ovarian cancers, and the same rationale that applies to breast and ovarian cancers applies to prostate cancers.

How do you determine whether to administer abiraterone or docetaxel across prostate cancer settings?

Data suggest that up to 30% of patients can benefit from PARP inhibition. Early data from the TOPARP study show very promising results with very high response rates and durable remissions. There are now 4 different PARP inhibitors in clinical trials in a variety of disease states; these trials are happening across the country, including at Mayo Clinic and other institutions. We're quite optimistic that we're going to see very positive results and bring an entirely new class of drugs to the armamentarium for prostate cancer. Chemotherapy still remains one of our key therapeutic modalities, but there's the whole question of sequencing. When do you administer a particular drug? When do you reach for hormone-based therapies versus chemotherapy, radium, or other therapeutic options? Both abiraterone and docetaxel are approved in the frontline setting for hormone-sensitive metastatic disease. There’s no easy answer as to whether patients should receive abiraterone or docetaxel; it’s very individualized to the patient. It depends on the patient’s disease state, disease burden, pace of disease, and tolerability.

What is your hope for the future standard of care in prostate cancer?

Data from the STAMPEDE study suggest that in the frontline setting, there is very little difference between the 2 agents in terms of overall survival. This was a secondary and underpowered analysis from the trial, so it’s not a definitive answer.Docetaxel is more toxic in the short-term. Most patients tend to favor abiraterone because it is a milder agent. Researchers are now trying to define the subsets of patients who will do better on chemotherapy than on abiraterone.Targeted therapies are being developed. We're starting to see more and more that there are definable biomarkers for response; the DNA-repair defects are one category. AR-V7 is another category that affect response to therapy. We have to keep in mind the statistic I cited earlier—8% to 12% of all metastatic patients have germline DNA-repair defects. That is 8% to 12% of patients who have something in their bloodline that's going to predispose their siblings and their children to breast, ovarian, pancreatic, and prostate cancers. I'm quite confident that in 2018, in the United States, only the smallest minority of patients are being tested. A new standard of care needs to include germline testing for DNA-repair defects for every patient with metastatic prostate cancer.

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 36, 2018 (suppl 6s; abstract 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).