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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical Genitourinary CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer.Prostate. 2010; 70: 1600-1607
- Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study.Sci Transl Med. 2015; 7 (269ra262)
Schweizer MT, Wang H, Luber B, et al. Bipolar androgen therapy for men with androgen ablation naive prostate cancer: results from the phase II BATMAN study. Prostate.2016;76:1218-1226.
- Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study.Lancet Oncol. 2018; 19: 76-86
- A multicohort open-label phase II trial of bipolar androgen therapy in men with metastatic castration-resistant prostate cancer (RESTORE): a comparison of post-abiraterone versus post-enzalutamide cohorts.Eur Urol. 2020; 79: 692-699
- TRANSFORMER: a randomized phase II study comparing bipolar androgen therapy versus enzalutamide in asymptomatic men with castration-resistant metastatic prostate cancer.J Clin Oncol. 2021; 39: 1371-1382
- Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements.Nat Genet. 2010; 42: 668-675
- Androgen-induced TMPRSS2:ERG fusion in nonmalignant prostate epithelial cells.Cancer Res. 2010; 70: 9544-9548
- Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage.J Clin Invest. 2019; : 130
- Durable response of enzalutamide-resistant prostate cancer to supraphysiological testosterone is associated with a multifaceted growth suppression and impaired DNA damage response transcriptomic program in patient-derived xenografts.Eur Urol. 2020; 77: 144-155
- Extreme response to high-dose testosterone in BRCA2- and ATM-mutated prostate cancer.Eur Urol. 2017; 71: 499
- Androgen receptor as a licensing factor for DNA replication in androgen-sensitive prostate cancer cells.Proc Natl Acad Sci. 2006; 103 (U S A): 15085-15090
- Stabilizing androgen receptor in mitosis inhibits prostate cancer proliferation.Cell Cycle. 2007; 6: 647-651
- DNA-repair defects and olaparib in metastatic prostate cancer.N Engl J Med. 2015; 373: 1697-1708
- ARID1A promotes genomic stability through protecting telomere cohesion.Nat Commun. 2019; 10: 4067
- ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors.Cancer Discov. 2015; 5: 752-767
- Participation of p53 protein in the cellular response to DNA damage.Cancer Res. 1991; 51: 6304-6311
- p53 status in the primary tumor predicts efficacy of subsequent abiraterone and enzalutamide in castration-resistant prostate cancer.Prostate Cancer Prostatic Dis. 2018; 21: 260-268
- Combined tumor suppressor defects characterize clinically defined aggressive variant prostate cancers.Clin Cancer Res. 2016; 22: 1520-1530
- Genomic correlates of clinical outcome in advanced prostate cancer.Proc Natl Acad Sci U S A. 2019; 116: 11428-11436
- The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.Cancer Discov. 2012; 2: 401-404
Article info
Publication history
Published online: August 15, 2021
Accepted:
August 10,
2021
Received in revised form:
May 14,
2021
Received:
March 22,
2021
Footnotes
Prior Presentation of Work: 2021 Genitourinary Cancers Symposium (GU ASCO).
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
