Aggressive Prostate Cancer Type Is 'Fairly Prevalent'

Nick Mulcahy

July 16, 2018

Many clinicians who treat men with prostate cancer may be unfamiliar with the term "treatment-emergent small-cell neuroendocrine prostate cancer" (t-SCNC).

That's because it has been considered a rare phenomenon, previously estimated to occur in about 1% of men with metastatic castrate-resistant prostate cancer (mCRPC).

However, a new study has found that it is present in nearly one fifth of men with mCRPC.

Rahul Aggarwal, MD, from the University of San Francisco, California, and colleagues found that among 202 men with progressive mCRPC who were consecutively enrolled at five US centers, the overall incidence of t-SCNC was 17%.

The new finding was published online July 9 in the Journal of Clinical Oncology.

The researchers note that t-SCNC, which may be a disease subtype, is associated with resistance to the androgen receptor (AR)–targeting agents  abiraterone (Zytiga, Janssen) and enzalutamide (Xtandi, Astellas/Pfizer), as well as to other hormonal treatments.

Notably, detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% confidence interval, 1.07 - 3.82). Median overall survival was 44.5 months in men without t-SCNC and 36.6 months in those with t-SCNC, among those who had prior use of abiraterone and/or enzalutamide (P = .027).

The finding that prior use of abiraterone and enzalutamide was tied to diminished survival among the men with t-SCNC should not be a complete surprise to clinicians, the authors suggest.

"Therapeutic resistance [to abiraterone and enzalutamide] is a near-universal phenomenon, frequently heralded by a more aggressive clinical course," they write.

"The main-take home point is that t-SCNC is fairly prevalent and that there are no hallmark clinical characteristics that can be used to identify this high-risk disease subset," Aggarwal told Medscape Medical News.

"It is probable that increasing use of abiraterone and enzalutamide may be leading to increased incidence of t-SCNC, but our study did not definitely address this question," he added.

The study could not address the issue because only a minority of patients had no previous  exposure to abiraterone or enzalutamide.

Specifically, 148 (73%) of the men in the study had prior disease progression on abiraterone and/or enzalutamide. Other study patients had disease progression on older forms of hormonal therapy, including luteinizing hormone–releasing hormone agonists, such as leuprolide (Lupron, AbbVie), as well as first-generation antiandrogens, such as bicalutamide, nilutamide, and flutamide.

Consider Metastatic Biopsies

In the study, the 202 men underwent a total of 249 metastatic tumor biopsies, including those of the bone, liver, lymph nodes, and other soft tissues. The median time from diagnosis of mCRPC to biopsy was 17.6 months.

Of the 202 men, 160 (79%) had sufficient tumor present in a biopsy specimen to permit histologic classification. t-SCNC was found in 27 of the 160 (17%).

This subtype resembles de novo small-cell prostate cancer, a highly aggressive histologic variant present in less than 1% of untreated prostate cancers at the time of diagnosis.

The study authors say that "it is not clear" whether the treatment-emergent variant is the same disease entity as de novo small-cell prostate cancer. As a result of this uncertainty, researchers have given this variant its own moniker: t-SCNC.

Other reports have attempted to define the prevalence and characteristics of this treatment-emergent variant but have been hampered by a lack of prospective data. However, one series of 150 men (with mCRPC and evaluable metastatic biopsy specimens) was prospective and, as noted above, tallied an incidence of t-SCNC of about 1% (0.7%) (Cell. 2015;161:1215-1228).

Aggarwal and his coauthors explain that this 2015 study is the best available comparator — but not a great one — because of multiple methodologic differences.

Aggarwal placed the current study in a larger context: "This was one of the first large, multicenter, prospective studies to analyze the incidence of t-SCNC in mCRPC using data from sequentially enrolled patients who did not previously carry a diagnosis of t-SCNC."

The implication for clinical practice, said Aggarwal, is that metastatic biopsies "should be considered broadly" in men with mCRPC who have tumors that are safely accessible for biopsy.

"We are observing an increasing prevalence of men who undergo tumor biopsy, but it remains an underutilized diagnostic tool outside of the academic setting," he added.

Metastatic biopsies allow for a better understanding of the histologic subtype (t-SCNC vs standard adenocarcinoma), as well as additional genetic information about the tumor.

It is important to try to identify the distinct subsets of mCRPC, said Aggarwal, "including those with t-SCNC, those harboring tumors with DNA repair defects, and potentially other subcategories, for purposes of new drug development and application of therapies with a higher degree of specificity for the tumor subtype."

Two transcription factor proteins found to be overactivated in t-SCNC in the study population are targets of drugs already in clinical trials, with several more in preclinical testing, Aggarwal said in comments online. However, no treatments targeting such factors or mutations in prostate cancer are currently available for use in the clinic.

The study was funded by the Prostate Cancer Foundation, Movember, and Stand up to Cancer. Multiple study authors, including Aggarwal, have financial ties to industry, including companies with prostate cancer products.

J Clin Oncol. Published online July 9, 2018. Abstract

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