Is Nonmetastatic Castration-Resistant Prostate Cancer a Valid Disease Category?

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Does nonmetastatic castration-resistant prostate cancer really exist? Although it is considered a disease category, it turns out that the definition depends on the type of imaging used. Many patients with castration-resistant prostate cancer who were categorized as “nonmetastatic” on conventional imaging turn out to have local and distant disease when using newer, more sophisticated techniques.

A. Oliver Sartor, MD

A. Oliver Sartor, MD

This clinical scenario is most evident in studies of prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) scans, which show that “almost 100% of patients with castration-resistant prostate cancer categorized as nonmetastatic actually had PSMA-positive lesions,” explained A. Oliver Sartor, MD, Medical Director of the Tulane Cancer Center, New Orleans.1

Imaging and Treatment Implications

“PSMA-PET scan is where the action is,” Dr. Sartor commented at the 2019 Annual Chemotherapy Foundation Symposium. “An application for approval will be submitted to the [U.S. Food and Drug Administration], and it will be approved eventually.”

PSMA exists exclusively on the surface of prostate cancer cells, so identifying these cells on imaging establishes the presence of cancer cells. PSMA-positive cells tend to be more aggressive, Dr. Sartor said.

Not only does PSMA-PET have diagnostic utility, but the PSMA-binding ligands have potential therapeutic applications. New therapies targeted to PSMA are in development; one of them, lutetium Lu-177 (Lu-177–PSMA-617), a radioligand using inhibitors of PSMA, is extremely promising, he noted. Recently, a phase II trial testing this agent has accrued more than 800 patients. Dr. Sartor and other prostate cancer experts are hopeful that these agents will represent a further advance in treating metastatic castration-resistant prostate cancer.

On conventional computed tomography scan or bone scan, prostate cancer can be easily categorized as metastatic or nonmetastatic, Dr. Sartor continued, but this category is murkier when newer imaging techniques are used. Patients who are deemed nonmetastatic on conventional imaging with a rising prostate-specific antigen (PSA) level are candidates for treatment with three newer U.S. Food and Drug Administration (FDA)-approved hormonal agents: apalutamide, enzalutamide, and darolutamide.

Dr. Sartor noted that questions arise with these patients: “Who are they? What determines their prognosis? What are the treatment options, and what are the implications of treatment?”

He focused his comments on asymptomatic patients defined solely as having castration-resistant prostate cancer by a rising PSA level on castrate levels of testosterone (ie, biochemical failure). The vast majority are treated with androgen-deprivation therapy for a rising PSA level after local definitive therapy with surgery or radiation therapy.

“Treating with androgen-deprivation therapy in this setting is a debatable indication. There should be some controversy about this. The indications for androgen-deprivation therapy are nebulous in the absence of metastatic disease. In my opinion, treating these patients with androgen-deprivation therapy with noncurative intent brings a special burden of responsibility and raises questions regarding efficacy/toxicity ratios,” stated Dr. Sartor.

“Regarding prognosis, a variety of studies recapitulate that the most important variable to predict prognosis in nonmetastatic castration-resistant prostate cancer is the PSA doubling time,” Dr. Sartor told listeners. “The relationship between prognosis and PSA doubling time is nonlinear. This has implications for when we treat patients. A slow or rapid PSA doubling time is not the same.”

Current treatment options for nonmetastatic castration-resistant prostate cancer include systemic therapies (older hormonal agents) or newer hormonal therapies added to androgen-deprivation therapy. “There is no doubt that newer FDA-approved therapies—such as apalutamide, enzalutamide, and darolutamide—are more active than androgen-deprivation therapy alone. It may be that abiraterone acetate is as effective as these drugs, but this has not been studied. In my opinion, abiraterone acetate would be quite effective if it were studied,” Dr. Sartor continued.

Chemotherapy does not have a role in treating asymptomatic nonmetastatic castration-resistant prostate cancer. Nonsystemic therapy, such as stereotactic body radiotherapy, may have a role in this setting for the treatment of molecular-staged disease, he suggested.

Trials of Newer Hormonal Agents

Dr. Sartor briefly reviewed three phase III trials that led to the approval of apalutamide, enzalutamide, and darolutamide, respectively.

The SPARTAN trial enrolled 1,207 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of up to 10 months.2 Patients were randomly assigned to receive apalutamide vs placebo (both groups were on background androgen-deprivation therapy). A significant 72% reduction in the risk of metastasis or death (P < .001) led to the approval of apalutamide.

“Although the median PSA doubling time was 4.4 months in this trial, the FDA did not use this metric for approval, and the drug was approved for patients with all PSA doubling times,” Dr. Sartor noted.

The PROSPER trial randomly assigned 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time up to 10 months to receive enzalutamide plus androgen-deprivation therapy vs placebo plus androgen-deprivation therapy, with the same endpoint as the SPARTAN trial.3 Enzalutamide reduced the risk of metastasis or death by 71%, again a highly significant difference from placebo (P < .001). The FDA broadened the approval label to include nonmetastatic castration-resistant prostate cancer without regard to PSA doubling time, even though the median PSA doubling time was 3.8 months.

The ARAMIS trial had a similar design and patient population and included 1,509 men randomly assigned to receive darolutamide plus androgen-deprivation therapy vs placebo plus androgen-deprivation therapy.4 Patients were stratified for PSA doubling time up to 6 months and longer than 6 months. Darolutamide reduced the risk of metastasis-free survival or death by 59% (P < .0001), which led to FDA approval of darolutamide without regard to PSA doubling time. In this trial, patients had a median PSA doubling time of 4.4 months.

Existence of Disease Category Questioned

So, again, does nonmetastatic castration-resistant prostate cancer really exist? Conventional bone scans and computed tomography scans detect tumors that are 1 cm, but 1-cm tumors may contain as many as 1 billion cells. Newer molecular imaging modalities are up to 100 times more sensitive than conventional imaging.

“If patients in these three trials had newer molecular imaging, the results could change our analysis of these trials, Dr. Sartor said. He acknowledged that this would not change the conclusions that apalutamide, darolutamide, and enzalutamide improve survival. “Molecular imaging will redefine ‘nonmetastatic castration-resistant prostate cancer,’” he predicted.


  • Nonmetastatic castration-resistant prostate cancer may not be a valid disease category.
  • More sensitive imaging with PSMA PET scan reveals that more than half of nonmetastatic prostate cancers, according to conventional imaging, are actually metastatic.
  • Many prostate cancer experts are excited about the potential of PSMA PET imaging to inform diagnosis and treatment selection.
  • New therapies directed against PSMA are in development.

Newer imaging modalities for bone and soft tissue include PSMA-PET (not yet approved), choline PET (FDA-approved), fluciclovine (F18, FDA-approved), and ­f­luorodeoxyglucose PET (approved but not in prostate cancer). “The most sensitive of these methods is PSMA-PET,” according to Dr. Sartor.

In a recent study, 98% of 200 patients with nonmetastatic castration-resistant prostate cancer on conventional imaging had positive PSMA-PET scans.5 Of these patients, 55% had metastatic disease, and 44% had pelvic disease recurrence alone, including 24% with local recurrence in the prostate bed. “Radiotherapy may play a role in treating prostate bed and pelvic recurrence, but the outcomes for metastatic lesion–targeted therapies are still unknown.”

Dr. Sartor continued: “The advent of newer hormonal agents used earlier in the course of disease is disrupting older treatment paradigms. Nonmetastatic castration-resistant prostate cancer is PSMA-PET–positive in the vast majority of cases with rapid PSA doubling times, but intervention based on molecular


For perspectives on outcomes for black and white patients with prostate cancer, see an interview with Sumanta K. Pal, MD, and A. Oliver Sartor, MD, on The ASCO Post Newsreels at

scans has not yet demonstrated clinically better outcomes. Earlier treatment is changing the landscape of metastatic castration-resistant prostate cancer dramatically.” Early results with PSMA-targeted therapy for PSMA-PET–positive disease are promising, and the prostate cancer community awaits the results of larger clinical trials.

The VISION trial has recently finished accruing 815 patients with metastatic castration-resistant prostate cancer on conventional imaging, but to enter the trial, imaging also included those who were PSMA-PET–positive. Treatments with abiraterone/enzalutamide and a taxane were required before trial entry. Patients are being randomly assigned to receive the standard of care, plus or minus Lu-177–PSMA-617, and the primary endpoints are radiographic progression-free survival and overall survival. Dr. Sartor is co-primary investigator of this trial.

Value of PSMA-PET Imaging

Charles G. Drake, MD, PhD

Charles G. Drake, MD, PhD

“PSMA-PET imaging is an extremely valuable imaging technology. It’s quite specific and more sensitive than conventional imaging such as computed tomography and bone scans. This is particularly important when PSA levels rise after surgery or radiation therapy, allowing us to distinguish local from distant recurrence,” commented Charles G. Drake, MD, PhD, Director of the Genitourinary Cancer Program and Co-Director of Cancer Immunotherapy Programs at the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York. 

DISCLOSURE: Dr. Sartor has received grant/research support from Bayer, Celgene, Dendreon, Endocyte, Innocrin, Invitae, Johnson & Johnson, Merck, Sanofi, and Sotio; and has served as a consultant for Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Bellicum, Blue Earth Diagnostics, Bristol-Myers Squibb, Celgene, Constellation, Dendreon, EMD Serono, Johnson & Johnson, Myovant Sciences, Pfizer, and Sanofi. Dr. Drake has received grant/research support from Aduro Biotech, Bristol-Myers Squibb, and Janssen; and has served as a consultant for Agenus, Dendreon, NexImmune, ImmuneXcite, Janssen, Lilly, Merck, Pierre Fabre, and Roche/Genentech.


1. Sartor AO: M0 castrate-resistant prostate cancer: Does it exist? 2019 Chemotherapy Foundation Symposium. Presented November 6, 2019.

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

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

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. Fendler WP, Weber M, Iravani A, et al: Prostate-specific membrane antigen ligand positron emission tomography in men with nonmetastatic castration-resistant prostate cancer. Clin Cancer Res. September 11, 2019 (early release online).