Molecular and Clinical Characterization of Patients With Metastatic Castration Resistant Prostate Cancer Achieving Deep Responses to Bipolar Androgen Therapy

Mark C. Markowski, Sushant Kachhap, Angelo M. De Marzo, Laura A. Sena, Jun Luo, Samuel R. Denmeade, Emmanuel S. Antonarakis

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Bipolar androgen therapy (BAT) is an emerging treatment strategy for men with metastatic castration resistant prostate cancer (mCRPC) whereby serum testosterone is cycled from supraphysiologic to near-castrate levels each month. BAT has been shown to induce clinical responses in a significant proportion of patients, some of which are extreme. We explored the clinical and molecular characteristics of patients with mCRPC who achieved deep responses to BAT. Methods: We conducted a retrospective analysis of patients with mCRPC treated with BAT at Johns Hopkins. We identified 22 of 114 (19%) patients with mCRPC who achieved ≥70% PSA reductions upon treatment with BAT. All patients were treated using 400 mg testosterone cypionate intramuscularly every 28 days, together with continuous LHRH agonist therapy. Clinical-grade DNA sequencing was obtained using commercially available assays. Results: Somatic next-generation sequencing was obtained for 15 of 22 (68%) patients. Of these 15 extreme PSA responders with sequencing data available, All 15 of 15 (100%) harbored a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene. Among the subset of patients with measureable disease (N = 15), 10 patients (67%) achieved an objective response including one patient with a complete response. The median radiographic progression-free survival of these deep PSA responders was 11.3 months (95% CI, 7.9-25.0 months). Conclusions: We observed an enrichment of TP53 and HRD mutations in mCRPC patients with extreme PSA responses to BAT, with durability lasting about a year. These data support the hypothesis that BAT may most benefit patients with DNA repair-deficient mCRPC. Further studies of BAT in biomarker-selected mCRPC populations (ie, TP53/HRD-mutated) are warranted.

Original languageEnglish (US)
JournalClinical Genitourinary Cancer
DOIs
StatePublished - Aug 1 2021
Externally publishedYes

Bibliographical note

Funding Information:
The project was supported by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins NIH grant P30 CA006973, R01 CA184012, Department of Defense (W81XWH1910724) and a PCF Young Investigator Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Publisher Copyright:
© 2021 Elsevier Ltd

Keywords

  • Biomarker
  • DNA repair
  • Homologous recombination deficiency
  • Next-generation sequencing
  • Testosterone

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