Shedding Light on Mechanisms of Resistance to Treatment of Metastatic Castration-Resistant Prostate Cancer

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ONE OF the pressing issues in metastatic castration-resistant prostate cancer is the development of resistance to therapies directed at the androgen receptor (AR), such as enzalutamide (Xtandi) and abiraterone acetate (Zytiga). Research is ongoing to identify mechanisms of resistance in the hope of developing strategies to overcome them.

David R. Wise, MD, PhD

David R. Wise, MD, PhD

David R. Wise, MD, PhD, of the Perlmutter Cancer Center, NYU Langone Health, New York, updated attendees at the 2018 Annual Chemotherapy Foundation Symposium about three recently discovered mechanisms of resistance to treatment with enzalutamide or abiraterone in patients with castration-resistant prostate cancer who have a rising prostate-specific antigen (PSA) level: AR-dependent, AR-independent, and cyclin-dependent kinase 12 (CDK12) mutations.1 More is known about the first two mechanisms, but the role of CDK12 mutations in developing resistance to AR-directed therapies is less clear, according to Dr. Wise.

“Most metastatic castration-resistant prostate cancer responds to hormone therapy and then develops resistance. With each subsequent line of therapy with AR-signaling agents [enzalutamide, abiraterone], response rates decrease,” Dr. Wise explained.

Until recently, therapy for prostate cancer has been focused on the androgen receptor, which is the best characterized and validated target in hormone-naive castration-resistant prostate cancer. Enzalutamide and abiraterone are often prescribed after castration resistance develops on androgen-deprivation therapy. Both of these agents inhibit activity of the androgen receptor— enzalutamide directly and abiraterone through downregulation of androgen biosynthesis. With the increasing use of these agents comes an increasing prevalence of resistance.

AR-Related Mechanisms of Resistance

DR. WISE described a useful framework for characterizing prostate cancer at disease progression. These cancers can be classified by AR status (ie, AR-high or AR-low) or by pathway alterations such as CDK12 mutations, homologous repair gene mutations, or mismatch repair deficiency. AR-high cancers can express androgen receptor splice variant 7 (AR-V7) and/or amplified full-length AR, whereas AR-low cancers include neuroendocrine prostate cancer and “double-negative” prostate cancer (AR-negative and neuroendocrine-negative prostate cancers), the latter of which expresses the DKK1 gene.

Proteolysis-targeting chimeras (PROTACs) are a new class of preclinical compounds with broad ligand-dependent target specificity. A new oral androgen receptor proteolysis-targeting chimera is being studied in prostate cancer and may hold promise for overcoming AR-dependent resistance.

“Among the most exciting new compounds are [proteolysis-targeting chimeras]. They are not in clinical trials yet, but these agents allow us, in a ligand-dependent fashion, to target a protein for destruction. Androgen receptor proteolysis-targeting chimeras have shown activity in enzalutamide-resistant mouse models. We look forward to seeing clinical trials testing proteolysis-targeting chimeras in AR-dependent metastatic castration-resistant prostate cancer resistant to enzalutamide or abiraterone,” Dr. Wise predicted.

A number of lines of research have implicated elevated AR-V7 levels as a biomarker of AR-dependent resistance. Men with AR-V7–positive prostate cancer seem to have worse outcomes with enzalutamide or abiraterone therapy than men with AR-V7–negative cancers, according to a small study from 2014.2 Likewise, data from the multicenter PROPHECY trial support the prognostic value of AR-V7 in metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone.3 A circulating tumor cell AR-V7 assay was used in the PROPHECY trial, which enrolled patients with high-risk metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone with prospective AR-V7 testing. Patients who were AR-V7–positive had significantly worse progression-free survival and overall survival than those who were AR-V7–negative.


  • Androgen receptor dependence
  • Androgen receptor independence
  • CDK12 mutations

“These data from a prospective trial validate AR-V7 as a treatment-specific prognostic marker for enzalutamide or abiraterone,” Dr. Wise said. “As a community, we are eager to see more data demonstrating that AR-V7–positive patients are more likely to benefit from chemotherapy.”

CDK12 Mutations

BIALLELIC CDK12 loss is rarely seen in localized prostate cancer, but it has recently been identified in about 7% of patients with metastatic castration-resistant prostate cancer, noted Dr. Wise. The hope is that CDK12 loss may predict response to checkpoint blockade.

A single-arm phase II trial is currently recruiting patients with CDK12-mutated metastatic castration-resistant prostate cancer treated with the combination of ipilimumab (Yervoy) at 1 mg/kg intravenously (IV) plus nivolumab (Opdivo) at 3 mg/kg IV every 3 weeks for 4 cycles followed by nivolumab maintenance therapy given at 480 mg IV every 4 weeks. Dr. Wise said that CDK12 mutations “may be a marker for development of resistance,” but further study is needed.

DKK1-Positive, Double-Negative Prostate Cancers

AR-NEGATIVE, neuroendocrine-negative prostate cancer is becoming increasingly prevalent and has been identified in up to 25% of autopsy specimens, noted Dr. Wise. He reported that the immunosuppressive cytokine DKK1 is upregulated in these specimens.

A phase Ib/IIa parallel-arm study soon to open at NYU Langone Perlmutter Cancer Center will investigate whether a DKK1-neutralizing antibody called DKN-01 as monotherapy or in combination with docetaxel is an effective therapeutic strategy in men with metastatic castration-resistant prostate cancer who have had one prior line of therapy and are DKK1-positive.

“DKK1 expression might predict response to DKK1 blockade. The idea is that the DKK1-neutralizing antibody will reactivate the immune system in men who develop resistance to prior therapy,” Dr. Wise explained.

DISCLOSURE: Dr. Wise is a paid consultant for Foundation Medicine and Leap Therapeutics.


1. Wise DR: Targeting treatment resistance in CRPC. 2018 Annual Chemotherapy Foundation Symposium. Presented November 7, 2018.

2. Antonarakis ES, Lu C, Wang H, et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 371:1028-1038, 2014.

3. Armstrong AJ, Halabi S, Luo J, et al: The PROPHECY trial: Multicenter prospective trial of circulating tumor cell AR-V7 detection in men with mCRPC receiving abiraterone or enzalutamide. 2018 ASCO Annual Meeting. Abstract 5004. Presented June 4, 2018.