“Prostate cancer aggressive variants deserve clinical trial attention.”

The most commonly recognized prostate cancer aggressive variant is a high-grade neuroendocrine carcinoma.  De novo neuroendocrine prostate cancer (NEPC) is very rare, and it is much more common to see treatment-emergent NEPC arise after treatment with androgen deprivation therapy.1, 2  Some of these tumors may exhibit small cell morphology, although that is not a uniform characteristic.  By immunohistochemistry, NEPC typically has low expression of prostate lineage markers (e.g. androgen receptor [AR], NKX3.1, and HOXB13), yet high expression of neuroendocrine markers ( e.g. synaptophysin, chromogranin, and INSM1).  For this disease, it is well accepted that platinum chemotherapy is the standard of care.  Beyond that, our therapeutic options are limited, without any clear standard in patients who have previously been treated with platinum chemotherapy.

Beyond NEPC, other distinct phenotypes of metastatic castration-resistant prostate cancer are being increasingly recognized by immunohistochemistry and gene expression profiling.3  In addition to AR-driven castration-resistant prostate cancer and high-grade NEPC, there is a AR low phenotype, a double negative phenotype, lacking both AR and neuroendocrine markers/signaling, and an amphicrine phenotype, in which both AR and neuroendocrine markers are present.  With the exception of the double negative phenotype, where fibroblast growth factor receptor signaling appears to be a major driver,4 good therapeutic targets are still being explored for these other phenotypic aggressive variants.

We are just starting to understand the molecular drivers of these aggressive variant prostate cancers and the resistant phenotype.  There are some hints that RB loss has an important role in facilitating neuroendocrine differentiation.5, 6  Cooperative loss of multiple tumor suppressor genes, such as RB1 and TP53, leads to an overall worse prognosis.  Yet, AR may remain active, and neuroendocrine differentiation is not an obligate consequence.There appears to be a higher proliferative rate, the elevation of DNA repair processes, and resistance to AR antagonists.  PTEN is another tumor suppressor gene that is not uncommonly lost in prostate cancer.  Compounded loss of 2 or more of PTEN, TP53, and RB1, leads to aggressive prostate cancer behavior with an increased risk of relapse and death.8

With the above description of phenotypic and genotypic prostate cancer aggressive variants, we have to realize that there is a venn diagram overlap between the molecular and phenotypic descriptors.  In the clinic, we often still use clinical descriptors to identify aggressive variant prostate cancers, such as having visceral metastasis, lytic bone metastasis, or high volumes of metastases in the setting of a low PSA.  Dramatic radiographic progression of disease without much PSA progression is also lumped in with aggressive variant prostate cancers, and NEPC is often not the aggressive variant identified.  Reference to the “anaplastic” criteria used to identify patient populations who do not quite have NEPC, but may be likely to respond to platinum chemotherapy are now being adapted to consider as eligibility for clinical trials in efforts to capture patients with aggressive variant prostate cancers.9

These “anaplastic” criteria for aggressive variant prostate cancers are now beginning to incorporate some of these prognostic molecular tumor suppressor genes.  From the original clinically-defined “anaplastic” prostate cancer set of patients, it was shown that combined alterations of RB1, TP53, and/or PTEN are more common than unselected metastatic castration-resistant prostate cancer.10  Given all the heterogeneous methods to identify aggressive variant prostate cancers, it does propose a challenge to lump patients together into trials for the development of novel therapeutics.  Yet, those of us that treat high volumes of prostate cancer patients, recognize these aggressive variants when we see them in the clinic, and it is important for us to study their clinical situation due to their aggressive disease, poor prognosis and lack of effective treatment options.

Below, I list some active trials for patients with aggressive variant prostate cancers, who specifically do not have the neuroendocrine subtype.  Previously, at the start of the Covid-19 pandemic, I published an article focused on trials available for those with NEPC.11  It is now time to draw attention to patients who do not meet NEPC criteria, but who harbor either a prostate cancer aggressive variant phenotypic or genotypic marker, knowing that prognosis is poor and treatment options are limited.  These patients should be accrued to the below trials and many more trials should be developed, as we gain a better understanding of the biology underlying prostate cancer aggressive variant disease.

Ongoing clinical trials including neuroendocrine cancers of the genitourinary tract

  • XmAb20717 alone or in combination with carboplatin and cabazitaxel for aggressive variant prostate cancer (NCT05005728)
  • Apalutamide plus cetrelimab in patients with treatment-emergent small cell neuroendocrine prostate cancer (defined as positive chromogranin and/or synaptophysin expression by IHC and/or RB1 loss of function mutation or deletion) (NCT04926181)
  • PLANE-PC: Pembrolizumab and Lenvatinib in neuroendocrine, aggressive variant or RB deletion/mutant advanced prostate cancer (NCT04848337)
  • CHAMP: Nivolumab, ipilumumab, carboplatin and cabazitaxel for neuroendocrine or aggressive variant prostate cancer (NCT04709276)
  • Randomized phase 2 trial of cabazitaxel, carboplatin and cetrelimab followed by niraparib with or without cetrelimab maintenance for aggressive variant or at least 2 of 3 RB1, TP53, PTEN altered metastatic prostate cancer (NCT04592237)
  • HPN328 for high grade neuroendocrine or DLL3 expressing prostate cancer (NCT04471727)
  • Erdafitinib and abiraterone acetate or enzalutamide for double negative prostate cancer (NCT03999515)
  • Pembrolizumab plus carboplatin and etoposide for first-line NEPC or pembrolizumab plus Lenvatinib or pembrolizumab plus vibostolimab for platinum pre-treated NEPC (NCT02861573)

*Note NEPC in this trial is defined as 1% or greater synaptophysin staining, hence minority component and/or amphicrine prostate cancer are eligible

Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington


  1. Beltran, H., Hruszkewycz, A., Scher, H., Hildesheim, J., Isaacs, J., & Yu, E. et al. (2019). The role of lineage plasticity in prostate cancer therapy resistance. Clinical Cancer Research, clincanres.1423.2019. 
  2. Aggarwal, R., Huang, J., Alumkal, J., Zhang, L., Feng, F., & Thomas, G. et al. (2018). Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. Journal Of Clinical Oncology, 36(24), 2492-2503.
  3. Labrecque, M., Coleman, I., Brown, L., True, L., Kollath, L., & Lakely, B. et al. (2019). Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. Journal Of Clinical Investigation, 129(10), 4492-4505. 
  4. Bluemn, E., Coleman, I., Lucas, J., Coleman, R., Hernandez-Lopez, S., & Tharakan, R. et al. (2017). Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling. Cancer Cell, 32(4), 474-489.e6. 
  5. Meacham, C., & Morrison, S. (2013). Tumour heterogeneity and cancer cell plasticity. Nature, 501(7467), 328-337. 
  6. Labrecque, M., Takhar, M., Nason, R., Santacruz, S., Tam, K., & Massah, S. et al. (2016). The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells. Oncotarget, 7(17), 24284-24302. 
  7. Nyquist, M., Corella, A., Coleman, I., De Sarkar, N., Kaipainen, A., & Ha, G. et al. (2020). Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress. Cell Reports, 31(8), 107669.
  8. Hamid, A., Gray, K., Shaw, G., MacConaill, L., Evan, C., & Bernard, B. et al. (2019). Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer. European Urology, 76(1), 89-97.
  9. Aparicio, A., Harzstark, A., Corn, P., Wen, S., Araujo, J., & Tu, S. et al. (2013). Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer. Clinical Cancer Research, 19(13), 3621-3630.
  10. Aparicio, A., Shen, L., Tapia, E., Lu, J., Chen, H., & Zhang, J. et al. (2015). Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers. Clinical Cancer Research, 22(6), 1520-1530. 
  11. Yu EY. Neuroendocrine Carcinomas of the Genitourinary Tract – Treatment Options Are Desperately Needed… Even During the COVID-19 Pandemic. Urotoday Clinical Trials Portal 2020; March 31, 2020.
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