Novel Agents Revolutionize Nonmetastatic CRPC Paradigm

Partner | Cancer Centers | <b>Mayo Clinic Cancer Center</b>

Alan H. Bryce, MD, discusses how novel agents have impacted the nonmetastatic castration-resistant prostate cancer space.

Alan H. Bryce, MD

Over the past 2 years, FDA approvals of 3 oral antiandrogen agents have transformed the nonmetastatic castration-resistant prostate cancer (CRPC) treatment paradigm, according to Alan H. Bryce, MD.

In February 2018, apalutamide (Erleada) became the first agent approved for this population. The approval was based on results of the phase III SPARTAN trial, which demonstrated a median metastasis-free survival (MFS) of 40.5 months with apalutamide in combination with androgen-deprivation therapy (ADT) compared with 16.2 months with placebo plus ADT (HR, 0.28; 95% CI, 0.23-0.35; P <.0001).1

Updated findings from SPARTAN presented at the 2019 ESMO Congress showed that apalutamide plus ADT demonstrated a 25% reduction in the risk of death versus placebo/ADT.2 At a median of 41 months of follow-up, results showed that the median overall survival (OS) was not reached in either arm, favoring apalutamide (HR, 0.75; 95% CI, 0.59-0.96; P = .0197), but the data were not found to be statistically significant due to a prespecified P value boundary of .0121.

Enzalutamide (Xtandi) was initially approved in 2012 for patients with metastatic castration-resistant disease who received prior docetaxel; however, in July 2018, the agent was granted approval for those with nonmetastatic CRPC based on data from the phase III PROSPER trial. Findings showed a median MFS of 36.6 months with enzalutamide/ADT compared with 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; P <.0001).3

Third came darolutamide (Nubeqa), which the FDA indicated for the same population in July 2019 following the ARAMIS trial, results of which demonstrated a 59% reduction in the risk of metastases or death with darolutamide/ADT versus placebo/ADT (HR, 0.41; 95% CI, 0.34-0.50; 2-sided P <.0001).4,5

“We can happily say the prostate cancer space is very active right now with lots of drugs being tested and rapid progress being made,” said Bryce.

In an interview during the 2019 OncLive® State of the Science Summit™ on Genitourinary Cancers, Bryce, an assistant professor of medicine, and chair of the Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, discussed these agents and how they have impacted the nonmetastatic CRPC space.

OncLive: What are the most significant updates in nonmetastatic CRPC treatment?

Bryce: In the last year, nonmetastatic CRPC has become a disease entity that physicians are more aware of due to the approval of 3 drugs. This is a disease state where patients have yet to develop visible metastases on imaging studies, but the prostate-specific antigen level is rising despite being on ADT. When that is happening, we know that the patient is generally going to progress to metastatic disease within the next 12 to 18 months.

Now, we have 3 fairly well-tolerated, antiandrogen oral therapies that have been approved for use in this space: apalutamide, darolutamide, and enzalutamide. The agents were [evaluated] in individual clinical trials, in which each of the 3 drugs were combined with ADT versus placebo/ADT with MFS as the primary endpoint. Importantly, all 3 drugs showed a meaningful delay to metastasis.

Although cross-trial comparisons are discouraged, could you compare these trials given the similar patient populations?

We do try to avoid cross-study comparisons. These were contemporaneous studies launched, accrued, and read-out at similar times, with similar study designs and minor technical differences.

Ultimately, the results were very similar, and there is not much difference between outcomes. All reported a median MFS of 3 to 4 years, which is significantly better than the comparator.

There are slight differences in toxicities and administration. Darolutamide is given twice daily; apalutamide and enzalutamide are given once daily. Perhaps there are differences in terms of quality of life for patients depending on toxicity, but we don't have head-to-head comparators.

It comes down to clinicians gaining experience with the drugs and recognizing which patients will benefit more with which agent.

Is toxicity the main factor you consider in selecting treatment?

I expect that in the United States, treatment selection is going to come down to payers and which drug is contracted with which insurance company. Ultimately, all 3 drugs are highly effective with similar results, so I don’t feel compelled to use one versus another. If a given insurance company tells me to use one drug over the others, I am OK with that.

Hopefully, we will see good financial assistance. That would drive the consideration, because these are certainly expensive drugs for patients. I’m inclined to use whatever is financially best for the patient.

What does sequencing look like with these agents?

I don't expect any of these drugs will work after the others. Cross-resistance should be expected; we’ve seen this in the metastatic setting. There has been a pattern for many years of trying to use one oral agent after another, despite [previous scientific reports that] there is cross-resistance. Now, we have more studies proving that point.

Once you use one of these oral agents, you typically get a couple years of [benefit]. Afterward, further oral antigen pathway inhibitors aren't going to be the next treatment. At that point, [I would] switch mechanisms to perhaps chemotherapy or radiopharmaceuticals.

What are the main challenges that remain in this space?

There are two principle challenges. One is the determining the definition of nonmetastatic. With new imaging modalities coming out and various sorts of PET scanning that are able to detect early-stage disease, should disease detected by PET alone qualify as nonmetastatic or metastatic?

These trials were based on CT scans and technetium-based bone scans. The answer on an evidence-based level is, “We don't know how to classify them.” Without question, patient's whose disease is only visible on PET scans would have been eligible for these studies because their disease was not visible on CT and technetium scans. Having said that, treating them as metastatic disease is justifiable considering the available agents in that space. After all, you can see metastatic deposits. The truth is, we don't have level 1 evidence to support either position.

What data from ongoing clinical trials in prostate cancer are highly anticipated?

There is an ongoing trial called AFT19 with apalutamide in [biochemically relapsed disease]. It is a 3-arm study of ADT alone versus ADT/apalutamide versus ADT/apalutamide/abiraterone.

Similar to the CHAARTED and STAMPEDE studies, AFT19 is trying to take effective agents and bring them earlier in the disease course, which could potentially lead to significant improvements in OS. Of course, we can't assume that and have to wait to see the results.

Beyond that, expect to see more studies happening where we are taking approved agents for metastatic castration-resistant disease and moving them into the hormone-sensitive and nonmetastatic setting.


  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; abstract 161). doi: 10.1200/JCO.2018.36.6_suppl.161.
  2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in patients with nonmetastatic castration-resistant prostate cancer: updated results from the phase III SPARTAN study. Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract 843O.
  3. 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). doi: 10.1200/JCO.2018.36.6_suppl.3.
  4. 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). doi: 10.1200/JCO.2019.37.7_suppl.140.
  5. Fizazi K, Shore N, Tammela T, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2019;380:1235-1246. doi: 10.1056/NEJMoa1815671.