Recent Genome Sequencing Data in Metastatic Prostate Cancer

Recent genome sequencing data in metastatic prostate cancer have led to some significant changes in how we think about advanced disease. Namely, the Stand Up 2 Cancer (SU2C) International Dream Team discovered that 23% of patients with metastatic castration-resistant prostate cancer harbor genetic alterations in genes that lead to homologous recombination deficiency (HRD) e.g. BRCA2, BRCA1, ATM, etc.1 Even more recently, our group at the University of Washington together with others have found 11.8% of patients with metastatic prostate cancer, both hormone-sensitive and castration-resistant, to harbor germline alterations in DNA repair genes.2 Interestingly, there was no clear association with patients diagnosed at a younger age or those with a family history of cancer. This has great implications, not only for possible therapeutic options but for genetic and family counseling.
As a result of these findings, Dr. Heather Cheng, at the University of Washington, collaborating with others launched the first genetics clinic dedicated to men with prostate cancer and those at risk. The goal of this clinic is to provide genetic/family counseling to patients and families with known or suspected germline cancer predisposition alterations and to identify and characterize new prostate cancer predisposition genes. The clinic also provides an important resource for patients with either cancer predisposition genes, or who might be at high risk for such, into important clinical trials involving prostate cancer treatment or early detection.

One example of agents in clinical trials for patients harboring HRD is poly-ADP ribose polymerase (PARP) inhibitors. Mutations in genes that are important for the repair of double-strand DNA breaks by HRD can lead to hypersensitivity of cancer cells to PARP inhibition. This is because PARP1 repairs single-strand breaks and inhibition of PARP1 in tumors with HRD are believed to lead to widespread double-strand breaks that cannot be repaired, resulting in cancer cell death via so-called synthetic lethality. Early data with the PARP1 inhibitor, olaparib, showed 88% of patients with HRD to respond to the agent either by soft tissue disease response, PSA decline or circulating tumor cell count decline.3 Now many trials are underway in prostate cancer, both in biomarker selected and unselected patient populations (see specific single-agent trials for metastatic castration-resistant prostate cancer highlighted below).

The point of this article is not only to bring awareness to our community for these exciting new clinical trials with PARP inhibitors but also to broaden awareness to the fact that these genetic alterations are common, both somatic and germline. As a result, our field needs to consider the significant reaction to this by initiating efforts around the world to address these findings. As next-generation sequencing becomes more frequently utilized, I believe that more high-risk prostate cancer clinics staffed with experts and genetic counselors will be needed to help address both familial and therapeutic implications of these widespread and clinically important findings. As we move forward, we must also be mindful of the fact that any agents that induce double-strand breaks may lead to hypersensitivity of cells where HRD is present. This would include agents like platinum, mitoxantrone, radium-223 and others, which we will highlight in future letters from the Clinical Trials Portal.

Trials of note:

1. Robinson D, Van Allen EM, Wu YM, et al.  Integrative clinical genomics of advanced prostate cancer.  Cell 2015; 161(5):1215-1228.

2. Pritchard CC, Mateo J, Walsh MF, et al.  Inherited DNA-repair gene mutations in men with metastatic prostate cancer.  N Engl J Med 2016; 375(5):443-453.

3. 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.