‘Non-metastatic castration-resistant prostate cancer’ (nmCRPC) applies to a wide variety of patients with different risks for disease progression. It refers to patients who have had primary therapy intended for cure who then experience a rising PSA while receiving initial hormone suppression, i.e., nmCRPC. The ‘non-metastatic’ status designates that despite a rising PSA while on ADT conventional imaging with CT and bone scan is negative for metastatic spread. Among this ‘non-metastatic‘ category are men who have features likely associated with early development of metastatic disease i.e., PSA doubling time < 10 months and Gleason score of >8. A treatment goal for this group would be to delay the occurrence of metastases, i.e., prolong metastases-free survival.

Non-metastatic castration-resistant prostate cancer in men with high-risk features is frequently metastatic on PSMA PET/CT scans.

This high-risk group was studied by Fendler et al, as reported in Clin Cancer Res. 2019. The study group comprised 200 men with high-risk nmCRPC who exhibited a rising PSA while on hormone suppression (ADT): i.e., PSA >2 ng/ml., PSA doubling time < 10 months and Gleason score > 8. All were negative for metastatic disease on conventional CT and bone scans. When studied with PSMA PET scans, pelvic disease was found in 44%, of which 24% had recurrence in the prostate bed and 55% had cancer spread beyond the pelvis: extra-pelvic nodes, 39%; bone, 24% and viscera disease, 6%.

Treatment options for non-metastatic CRPC:

1)  Continue therapy with ADT until conventional imaging detects metastases and then augment ADT with second generation androgen receptor inhibitors (SGARi) – apalutamide, enzalutamide, darolutamide or the steroidogenesis inhibitor abiraterone. Or… initiate a SGARi if the PSA doubling time is <10 months.

2)  Perform a PSMA PET scan and, upon detecting metastases, augment ADT with a SGARi. The establishment of metastatic CRPC opens additional therapeutic options: Provenge, Bipolar Androgen Therapy (BAT) or metastasis directed therapy (MDT). 

A caveat: A thoughtful reflection on option #1 above was presented by Madan et al., Journal of Clinical Oncology, March 2024: “Restaging with Prostate-Specific Membrane Antigen Imaging in Metastatic Castration-Resistant Prostate Cancer: When Seeing More is Detrimental to Care.” They “seriously question if identifying subtle, likely subclinical changes on PSMA imaging translates into improving care” in patients with nmCRPC. Their recommendation is to base any therapeutic switch on disease progression exhibited on CT or bone scan. They note that in nmCRPC [i.e., early in the course of the disease] the PSA can rise over a duration of 17 months without evidence of progression on conventional imaging. Madan’s position is that a premature switch of therapy based on a PSA rise, or PSMA imaged metastases, should be withheld until research data demonstrates a clinical gain, otherwise the patient is at risk for sustaining adverse side effects without a commensurate survival benefit. A comparison of PSMA and standard imaging in biochemically recurrent prostate cancer is underway in a Clinical Trial, NCT04777071.

 Comparison of outcome and quality of life with systemic therapies in men with nmCRPC whose PSA doubling time is < 10 months.

This was addressed by Shore et al. in “A multidisciplinary approach to address unmet needs in the management of patients with non-metastatic castration-resistant prostate cancer,” Prostate Cancer and Prostatic Disease, March 2024.

Shore summarized the goals of treatment for nmCRPC as “delay or prevent metastatic disease and the need for additional antimetastatic treatment, maintain quality of life and prolong survival.”  In short, in this high-risk group apalutamide, enzalutamide and darolutamide all increased metastasis-free and overall survival when added to ADT. They all performed equivalently. The choice among the three is influenced by the adverse effects associated with each. Since there has been no “head-to-head” comparison, Shore’s article offers a consensus opinion based on “a panel of 10 multidisciplinary experts:”

Findings: Fatigue is a common feature of all three drugs: 32.6% for enzalutamide; 30.4%, apalutamide; 12.1% darolutamide — all greater compared to Lupron.

Other adverse effects:

  • apalutamide (Erleda) – rash, 23.8%; falls 15.6% seizures, 0.2%
  • darolutamide (Nubeqa) – back pain, 8.8%; arthralgia, 8.1%; seizures, 0.2%
  • enzalutamide  (Xtandi) – hot flashes, 13%; hypertension, 11.9%; falls, 11.4% and nausea, 11.4%. Seizure rate is comparably low.

Their comparison found “a stable long-term safety profile for darolutamide, whereas the likelihood … for serious adverse effects increased with apalutamide and enzalutamide.” Discontinuation of treatment was least likely with darolutamide, 33 months as compared to enzalutamide and apalutamide, 20.8 and 18.5 months, respectively. (George et al., JCO, 2023).

Drug-drug interactions are of significance and common in the older population commonly taking these drugs. The listing in the article is extensive. A consultation with a pharmacist is appropriate to evaluate and advise regarding a patient’s potential adverse drug-drug interactions.

To be noted: The high-risk for recurrence in the men studied in Fendler (above) and evaluated by Shore (also above) share similar high-risk features, suggesting that the ‘non-metastatic’ patients in Shore, if evaluated by PET/CT, would most likely be PET positive for metastatic CRPC.

A Counterintuitive relationshipCT progression associated with a non-rising PSA in late disease.

Encompassed in the Shore article is the statement: “ … a substantial proportion of patients using SGARis may experience disease progression without rising PSA levels.” (Italics mine) This counterintuitive finding was reported initially and analyzed in 2017 in “Radiographic progression with non-rising PSA in metastatic castration-resistant prostate cancer: a post hoc analysis of [the] PREVAIL [trial]” (Bryce et ai, Prostate Cancer and Prostatic Diseases, 2017). The PREVAIL trial compared enzalutamide to inert placebo pills in men with metastatic progression after initial hormone therapy as diagnosed by CT, bone scan and MRI. Bryce reported that “among 265 patients with radiographic progression, 65 (24.5%) had non-rising PSA levels.”

In their study one-third of men with non-rising PSA, but with progression on imaging, had visceral disease, a common feature in men with neuroendocrine prostate cancer, either mixed with adenocarcinoma or pure NEPC. Whereas PSMA PET scans do not register NEPC because of the lack of the PSMA target, in CT scans the physical presence of lesions containing NEPC are imaged.

With available data in 2017, Bryce et al. could only speculate that CT progression without PSA increase resulted from an admixture of adenocarcinoma and NEPC in which the NEPC lesions were CT apparent but not secreting PSA. In the future when the epigenetic test, “NEMO”, devised by Bartran (discussed in Commentary #187) becomes commercially available the extent of NEPC in this mixed situation can be assessed on circulating tumor DNA.


Men with ‘non-metastatic’ CRPC at high risk for recurrence, when scanned with a PSMA PET, will be found to have metastatic CRPC in nearly all cases. Men designated as ‘nmCRPC’ and those men established as having metastases, are equally responsive to the addition of second-generation androgen receptor inhibitors when added to ongoing ADT.