Response to Bipolar Androgen Therapy and PD-1 Inhibition in a Patient with Metastatic Castration-Resistant Prostate Cancer and a Germline CHEK2 Mutation - Beyond the Abstract

We are excited to report the case of our patient with metastatic castration-resistant prostate cancer (mCRPC) refractory to several lines of therapy who showed a dramatic response to bipolar androgen therapy (BAT), followed by pembrolizumab.

Our patient was diagnosed with prostate cancer in his early 40s. He was later discovered to harbor a mutation in CHEK2, which encodes a checkpoint kinase involved in DNA repair and has been implicated in hereditary prostate cancer. Over the course of approximately 20 years, he relapsed and progressed through nearly all standard of care therapies and some targeted and experimental treatments. These were as follows: brachytherapy, external beam radiation, androgen deprivation therapy (ADT) with leuprolide, combined androgen blockade with bicalutamide and then abiraterone, sipuleucel-T, surgical resection, lirametostat, olaparib, docetaxel, cabazitaxel, carboplatin, and palliative radiation therapy.

With a worsening burden of metastatic disease, hospice was being considered. Our report includes a poignant narrative from the patient, in which he exclaims that “the situation was bleak!” It was at this point that a novel treatment, BAT, was considered for off-label treatment. While androgen deprivation has been a cornerstone of prostate cancer therapy for decades, BAT exposes patients to rapid cycles of castration levels of androgen deprivation alternating with supraphysiologic levels of testosterone from exogenous supplementation. This approach had shown safety and a signal for efficacy in the phase 2 TRANSFORMER study.

The patient’s PSA rapidly declined, and interval imaging showed substantial reduction in metastatic tumor burden. Informed by the results of the COMBAT-CRPC trial, consolidation therapy with pembrolizumab was also pursued. The patient enjoyed an improved quality of life, remarking in his narrative that he could “spend quality time with [his] family and friends, “continue to work,” and even “hit the links a couple of times per week.” BAT has been shown to induce DNA damage in prostate cancer cells, and we speculate that the patient’s inherited DNA repair deficiency from CHEK2 mutation may have sensitized him to this therapy.

Unfortunately, the patient developed checkpoint inhibitor pneumonitis and later had progression of disease. In retrospect, the pembrolizumab may not have contributed to his response, as 3 phase 3 trials of pembrolizumab in men with mCRPC and metastatic hormone-sensitive prostate have recently been reported as negative.

He passed away 21 months after initiation of BAT/pembrolizumab. This was significantly out of proportion to his prior expected survival of less than 6 months, which motivated the case report. We recognize that this is a single case and it should not be used as evidence of efficacy for this approach. Further investigation is needed - and warranted - to evaluate BAT (with or without checkpoint inhibitors) in patients with mCRPC and inherited DNA repair deficiencies. We encourage readers to access the case report, especially noting the meaningful perspective contributed by the patient. His selflessness and courage continue to inspire us.

Written by:

  • Benjamin Berger, MD, Department of Medicine, Duke University Medical Center, Durham, North Carolina
  • Matthew Labriola, MD, Department of Medicine, Duke University Medical Center, Durham, North Carolina
  • Emmanuel Antonarakis, MD, Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA
  • Andrew Armstrong, MD, MSc, Duke Cancer Center and Duke Cancer Center Genitourinary (GU) Clinic, Duke University, Durham, North Carolina
Read the Abstract