Nonmetastatic Castration-Resistant Prostate Cancer

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Nonmetastatic castration-resistant prostate cancer arises in the subset of men with biochemically recurrent disease (ie, rising prostate-specific antigen [PSA] level after definitive therapy in the absence of metastases) who develop PSA progression after chronic exposure to androgen-deprivation therapy. The U.S. Food and Drug Administration (FDA) granted approval to two androgen receptor antagonists—enzalutamide (PROSPER study) and apalutamide (SPARTAN study)—as treatment of nonmetastatic castration-resistant prostate cancer. These approvals are based on phase III studies demonstrating improvements in metastasis-free survival—a novel intermediate endpoint shown to serve as a surrogate for overall survival in patients with hormone-sensitive prostate cancer.1-3

The ARAMIS trial4 adds to the growing body of evidence showing that AR-signaling inhibitors can delay metastasis in this subgroup of patients. [Editor’s note: On July 30, 2019, the FDA approved darolutamide (Nubeqa) on the basis of this trial.]

Given the expanding array of drugs demonstrating benefit in nonmetastatic castration-resistant prostate cancer, it is worthwhile to step back and examine the differences and similarities among the various agents shown to prolong metastasis-free survival in this space. All three studies (PROPSER, SPARTAN, and ARAMIS) mandated a PSA doubling time up to 10 months, on the basis of data showing that this group had a shorter metastasis-free interval than those with a PSA doubling time of 10 months or more.5 For the purpose of these trials, baseline M0 status was defined using conventional bone and computed tomography (CT) scans, with all studies allowing for small pelvic lymphadenopathy. In regard to the primary endpoint, all three studies showed remarkably similar results, with hazard ratios (HRs) for metastasis or death favoring enzalutamide (P < .001), apalutamide (P < .001), and darolutamide (P < .001) over placebo.

Darolutamide has a distinct molecular structure compared with enzalutamide and apalutamide. Preclinical studies have shown that darolutamide has decreased blood-brain barrier penetration compared with these other agents, which may offer advantages in terms of its toxicity profile.4 Consistent with this mechanism, there was no increased incidence of seizure, falls, fracture, or cognitive disorders in men receiving darolutamide compared with placebo in the ARAMIS trial.

However, caution should be taken in overinterpreting these results. Specifically, we should not conclude that darolutamide is safer than apalutamide or enzalutamide, given these agents have not been compared head-to-head to assess differences in toxicity. It is important to note that quality of life was found to be similar in all three studies when the experimental agent was compared with placebo.

Early Use of Agents And Drug Resistance

A key issue warranting close attention is whether the use of potent AR-signaling inhibitors early will result in more drug resistance later in the disease course. The PROSPER and SPARTAN studies attempted to address this concern by examining the time to second progression-free survival (progression-free survival-2), defined as the time from initial randomization to disease progression on the agent used immediately after treatment with enzalutamide or apalutamide, respectively. Although progression-free survival-2 data were initially not reported for the ARAMIS trial, both the PROSPER and SPARTAN trials showed that progression-free survival-2 favored the early use of potent AR-signaling inhibition. These progression-free survival-2 data are encouraging; however, it is important to recognize a more informative means for evaluating cross-resistance would have been to assess progression-free survival from the time of switching therapy as opposed to the time from initial randomization.

This may be a moot point, however, considering that SPARTAN, PROPSER, and ARAMIS all show trends in overall survival favoring the early use of AR antagonists for nonmetastatic castration-resistant prostate cancer.

Shifting Definition of the Nonmetastatic State

Another issue likely to influence the use of these agents is the means by which the M0 state is defined. The current dogma is that a persistently rising PSA level after definitive local therapy indicates residual micrometastatic disease. It stands to reason that the absence of metastatic cancer on conventional imaging is likely due to a lack of sensitivity of CT and bone scans. With the advent of next-generation positron-emission tomography (PET) imaging modalities (eg, prostate-specific membrane antigen and fluciclovine PET), we are now able to detect metastatic prostate cancer earlier, thus shifting our definition of the nonmetastatic state.

However, the clinical significance of finding cancer with one of these newer imaging modalities has yet to be defined. It is unknown whether patients with disease detectable with these next-generation imaging studies alone are best served by receiving an AR antagonist per PROSPER, SPARTAN, or ARAMIS, or they should be managed with drugs previously shown effective for patients with M1 castration-resistant prostate cancer.6 Additional prospective trials are needed to clarify the best treatment approach for these men.

‘Strong Evidence’ of Benefit

Including the ARAMIS study, we now have level 1 evidence from three large randomized studies that the early use of next-generation AR-signaling inhibitors can delay the time to metastases in men with nonmetastatic castration-resistant prostate cancer. Given the morbidity associated with metastatic cancer, effective strategies to delay the development
of overt metastatic disease represent a major advance in the field. There is strong evidence that enzalutamide, apalutamide, and darolutamide benefit the population of men with nonmetastatic castration-resistant prostate cancer. 

Dr. Schweizer is Assistant Professor, Department of Internal Medicine, Division of Medical Oncology, University of Washington School of Medicine, and Assistant Member of Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle. Dr. Lin is the Bridges Endowed Professor in Prostate Cancer Research; Professor and Chief, Urologic Oncology, University of Washington; and Associate Member of Fred Hutchinson Cancer Research Center, Seattle.

DISCLOSURE: Dr. Schweizer is a paid consultant/advisor with Janssen and has received institutional research funding from Janssen, AstraZeneca, Zenith, Pfizer, and Hoffmann–La Roche. Dr. Lin has received institutional research funding from Genomic Health, GenomeDx, and MDxHealth.


1. Hussain M, Fizazi K, et al: Enzalutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 378:2465-2474, 2018.

2. Smith MR, Saad F, et al: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 378:1408-1418, 2018.

3. Xie W, Regan MM, Buyse M, et al: Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol 35:3097-3104, 2017.

4. Fizazi K, Shore N, Tammela TL, et al: Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 380:1235-1246, 2019.

5. Smith MR, Saad F, Oudard S, et al: Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: Exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol 31:3800-3806, 2013.

6. Vapiwala N, Hofman MS, Murphy DG, et al: Strategies for evaluation of novel imaging in prostate cancer: Putting the horse back before the cart. J Clin Oncol 37:765-769, 2019.

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