Dr. Agarwal Discusses DNA Damage Repair Mutations in Prostate Cancer

Neeraj Agarwal, MD, discussed a study that will be presented during the 2021 ASCO Annual Meeting, Concordance of DNA damage repair (DDR) gene mutations in paired primary and metastatic prostate cancer (PC) samples.

GU Oncology Now: What are the key takeaways from the study?

Dr. Agarwal: So in this study, the team from the University of Washington led by Dr. Mike Sweitzer asked the question if there is a concordance of DNA damage repair gene mutations in Baird primary and metastatic prostate cancer samples. They wanted to establish if DDR mutations, which are seen on the metastatic prostate cancer samples, either in metastatic tissue, all circulating tumor DNA, are they also present in the primary prostate tissue? So just to establish if these mutations are only truncal events or they arise later.

Did any of the study’s findings surprise you?

I don’t think they were surprising. I think this has been our observation, also. We presented a similar abstract in the 2021 Genitourinary Oncology symposium in our collaboration with the garden 360. So not surprising, but I think these are very practiced informing a data, in the sense that if you have metastatic tissue, we can reliably say that this will likely replicate the findings from the primary tissue, or if you have circulating tumor DNA tissue results, sequencing results, I think I can assure my patients that this is what we are also going to see in the primary prostate tissue and vice versa. So not surprising, but I think practice informing.

Can you provide any insight on DNA damage repair gene mutations to help guide treatment options for men with prostate cancer?

Absolutely. I think role of PARP inhibitors are very clear for our patients, in treatment of our patients with metastatic prostate cancer. Up to 20% or 25% patients with metastatic castrate-resistant prostate cancer have DNA repair mutations in their tumors or in germline. And with the approval of Olaparib based on PROfound trial last year, and then recovery based on the TRITON 2 trial, we have these drugs available for our patients with metastatic castrate-resistant prostate cancer. Olaparib is approved for those patients who have had disease progression after one novel hormonal therapy. Rucaparib is approved for our patients who have had disease progression after novel hormonal therapy and a chemotherapy such as docetaxel.

So now we have these drugs approved and they improve overall survival, especially with Olaparib. It showed improved overall survival and radiographic progression free survival in a randomized control trial. Through copper, it was approved with response rates, objective response rates, comparable to other PARP inhibitors. So we have these highly well-tolerated oral therapy options for our patients. So we do not have any reason for not looking for these mutations, these DNA repair mutations in our patient’s tumor tissue or angioma. So yes, these are very important findings from the perspective of how we treat our patients in the clinic.

For what patient population could the analysis of DDR gene mutations be useful?

That’s a great question. People often wait for onset of castrate-resistant metastatic prostate cancer before ordering germline or somatic tissue sequencing to look for these DNA repair mutations. In my view, we should not wait. I never wait to sequence. I ordered these sequencing testing when I see the patient for the first time. We know that especially primary tumor tissue may lose the quality to allow proper sequencing. And there is a time limit for most of these testings. Most of these companies, especially commercial vendors, they do not accept tissue, which is six years or older, more than six years old.

Many times we know, based on our personal experience, that these tissue are not kept by the hospitals, local hospitals for more than 10 years. And instead of waiting for onset of castrate-resistant prostate cancer, and then try to do sequencing when these tissues may lose, we may lose the quantity or quality of these tissue. I think at least in my practice, I order solid tumor sequencing of primary or metastatic tumor tissue, or both are circulating tumor DNA. Pretty much when I see these patients for the first time. And that’s what I would suggest to my colleagues and across the world to sequence, do not delay sequence.

What is your final takeaway from this abstract, from the perspective of being on the steering committee of the PROfound trial, which led to approval of first PARPi olaparib for men with metastatic prostate cancer?

Absolutely. So, first of all, if you look at the PROfound trial, this was the first randomized phase three trial in metastatic prostate cancer, which was biomarker based, and it was positive. So great news indeed for our patients, which led to approval of Olaparib, the first PARP inhibitor for treatment of patients with metastatic prostate cancer. What we really learned from this trial was the first thing from this perspective, 30% patients were not eligible even for screening for the trial because they did not have adequate quantity or quality of tissue. So patients had progressive disease and we want to look for qualifying DNA repair gene mutations.

And we did not have too much tissue for those patients. And this happened because those tumor tissue were either too old or not available. So the biggest lesson I learned from the PROfound trial, other than that, Olaparib is a very valid option phase based on a randomized phase three trial backed by level one evidence, that we should not wait for our patients to develop castrate-resistant disease before we order comprehensive genomic profiling of the tumor tissue or the circulating tumor DNA or both. I think we should order them the first time we see our patients, especially with the tumor tissue, which loses quality and many times they’re not simply available after a given duration. They get thrown away or somehow they get lost.

So I think those are the two most important messages I learned from the PROfound trial.