Implications of Genomic Analysis for mCRPC
A recently published study highlighted the impact of genomic profiling and oncological outcomes.1 This study obtained 444 samples from 429 mCPRC patients, of which 128 patients were treated with a first-line next-generation androgen receptor signaling inhibitor (abiraterone or enzalutamide). Among 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor variant expression, androgen receptor transcriptional output, and neuroendocrine expression signatures, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with a shorter time on treatment with abiraterone or enzalutamide.
The homologous recombination deficient tumors are of particular interest among patients with mCRPC. In a single-arm phase 2 trial (n = 50), patients in the TOPARP-A, a Phase II Trial of Olaparib in Patients With Advanced Castration-Resistant Prostate Cancer (TOPARP) trial who were previously treated with docetaxel and prior enzalutamide/abiraterone had antitumor activity of olaparib (400mg BID) against molecularly unselected mCRPC patients.2 TOPARP-B was a phase II trial for patients with mCRPC preselected for putatively pathogenic DNA damage repair alterations, randomizing 98 patients 1:1 to 400mg or 300mg of olaparib BID.3 The primary endpoint of response rate was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to < 5), confirmed after 4-weeks. The overall response rate was 54% (95%CI 39-69%), meeting threshold for primary endpoint) in the 400 mg cohort and 39% (95%CI 24-54%) in the 300 mg cohort.
Previously, pembrolizumab was approved by the U.S. Federal Drug Administration (FDA) for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors. In a study by Abida et al.4 assessing the prevalence of MSI-H/dMMR in prostate cancer, they found that 23 of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional nine patients had indeterminate scores with evidence of dMMR. Furthermore, 7 of the 32 MSI-H/dMMR patients had a pathogenic germline mutation in a Lynch syndrome-associated gene. Eleven patients with MSI-H/dMMR CRPC received anti–PD-1/PD-L1 therapy and six of these patients had a greater than 50% decline in PSA levels, four of whom had radiographic responses:
Dr. Gulley notes that tumors with mixed or overlapping features expressing both androgen receptor and androgen receptor pathway genes, as well as neuroendocrine markers, or those lacking both androgen receptor and neuroendocrine markers (ie. “double negative” tumors) may further represent distinct disease states or a continuum.5 This is highlighted in the subsequent figure:
Dr. Gulley concluded his presentation noting that genomic testing should be done for all patients with mCRPC, as this allows precision medicine for these patients and targeted therapy based on their genomic profile:
Presented by: James Gulley, MD, PhD, Director of the Medical Oncology Service at National Cancer Institute, Bethesda, Maryland
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2020 American Urological Association (AUA) Annual Meeting, Virtual Experience #AUA20, June 27- 28, 2020
- Abida W, Cyrta J, Heller G, et al. Genomic Correlates of Clinical Outcome in Advanced Prostate Cancer. Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11428-11436.
- Mateo J, Carreira S, Sandhu S, et al. DNA-Repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708.
- Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomized, phase 2 trial. Lancet Oncol 2020 Jan;21(1):162-174.
- Abida W, Cheng ML, Armenia J, et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol 2019 Apr 1;5(4):471-478.
- Beltran H, Hruszkewycz A, Scher HI, et al. The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance. Clin Cancer Res 2019 Dec 1;25(23):6916-6924.