PARP Inhibitors, Prostate Cancer and a Promise Fulfilled

June 26, 2020, marked the 20th anniversary of the publication of the first working draft from the Human Genome Project. At a special White House event to commemorate the results of this 10-year public effort (it was really more like 50 years since the discovery of DNA, but I digress), then-President Bill Clinton called the project “the most wondrous map ever created by humankind”, and touted its promise to detect, prevent, and treat disease.  Obtaining that first sequence from one human cost about $2B and resulted from a massive global public/private partnership.

Today, you can get a full human genome for about $200 and we know the full genome of close to 2500 species.1 We now can capture and sequence a full novel genome with incredible speed and accuracy. This was evidenced recently: recall that the first recognition of the deadly clinical potential of the COVID 19 pandemic was in January … and we had its full genome by early March! Even though the world still struggles against this novel virus, science has a map to a vaccine and to a cure. 

Science can move at an incredible pace when the attention of many is focused on one problem or question. In a similar fashion, our deep understanding of the human genome can now help us to counsel and treat patients. Thanks to commercially available assay kits stocked on the shelves of our clinic, we can do it on a daily basis. That’s incredible when you think about it.  At the time the human genome project was compared in magnitude to the Apollo Space program. But as I see it,  rather than take a handful of humans on a major scientific mission, it brings a major scientific mission to potentially billions of individuals. And right there in the palm of your hand in your daily clinic.

Our understanding of the genome has transformed oncology, as we now must consider Neurotrophic Tropomyosin-Related Kinase (NTRK) fusions, epidermal growth factor receptor (EGFR) mutations, and Kirsten ras sarcoma viral oncogene homolog (KRAS) status routinely in the evaluation of patients. Yet, much of that has not yet reached prostate cancer. But it is here now. As of May 2020, we have the first therapeutic choice in metastatic castration-resistant prostate cancer (mCRPC) which is a direct result of the genome project – the poly-ADP ribose polymerase (PARP) inhibitors olaparib and rucaparib. 

Practicing genomics-guided medicine is a new skillset that one must acquire. We, clinicians, need to know when to do it, how to do the testing, and how to implement therapies as a result of it. Further, as with any new therapeutic class, we need to know what to tell our patients to expect in terms of efficacy and safety.

I am therefore proud to present a series of guest pieces by three rising stars in GU Oncology who will define the role of PARP inhibitors in the future of prostate cancer management, and guide clinicians through the questions posed above. 

In the first, Veda Giri, MD, Associate Professor at the Thomas Jefferson School of Medicine and Kimmel Cancer Center, walks us through who should be considered for germline genetic testing, what kinds of tests we can consider ordering, and how to interpret them. 

In the second, Patrick Pilié, MD, Assistant Professor of Cancer Medicine at MD Anderson Cancer Center gives us an approach to the consideration of somatic (tumor based results), how they differ, and can reveal more than germline results, and some of the pitfalls in their interpretation.  

Finally, Arpit Rao, MBBS, Assistant Professor of the University of Minnesota introduces us to some of the clinical nuances this new class of therapy places in front of us, how we confront them practically, and what to expect. 

Practicing oncology has never been more interesting or gratifying. The ability to do so comes with an obligation to evolve to where the science takes you. Those of us who do research on the development of these agents are equally excited about the benefits they offer, and also taking on the challenge of discovering their limitations and developing responses to them. In the meantime, we hope that these essays by Giri, Pilie, and Rao, as well as the video roundtable on UroToday.com aid in facilitating the dissemination of knowledge and the facility with which PARP inhibitors can be used, bringing the promises made over 20 years ago to your clinic and your patients. 

Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Director and Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota

References: 

  1. McKie, Robin. ‘The wondrous map’: how unlocking human DNA changed the course of science. The Guardian. June 21, 2020. Retrieved from: https://www.theguardian.com/science/2020/jun/21/human-genome-project-unlocking-dna-covid-19-cystic-fibrosis-molecular-scientists

Related Content:
  1. Germline Testing for DNA Repair Mutations in Prostate Cancer: Who, When and How?
  2. What Are the Most Common Genomic Aberrations Seen in DNA Damage Response (DDR) Pathways in Advanced Prostate Cancer?
  3. PARP Inhibitors - A Breakthrough in Targeted Therapies for Prostate Cancer
  4. DNA Repair and PARP Inhibitor Therapy in Prostate Cancer - Veda Giri, Patrick Pilié, and Arpit Rao

Published Date: June 2020