PROfound: Olaparib for Metastatic Castrate Resistant Prostate Cancer - Thomas Keane

July 2, 2020

Thomas Keane highlights the PROfound Study, Olaparib for Metastatic Castrate Resistant Prostate Cancer, published in the New England Journal of Medicine this year. The study found that in men with metastatic prostate cancer with genetic alterations relating to homologous recombination repair who have shown disease progression while receiving ezalutamide or abiraterone, olaparib was associated with longer progression-free survival. Dr. Keane recaps the study suggests a significant role for genetic testing in this disease space going forward, emphasizing that this is something that urologists should continue to focus on in the future.


Thomas E. Keane, MBBCh, FRCSI, FACS, Department of Urology, The Medical University of South Carolina, Charleston, South Carolina, USA.

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Thomas Keane: Good morning everybody, this is Tom Keane coming to you from UroToday. I'm from the Medical University of South Carolina in Charleston. As we deal with this crisis that we're slowly coming through, we're learning more about it.

Because of it, I'm coming to you bringing you abstracts, which were to be presented at the American Urology Association meeting this year, and they will not be now, but The Journal of Urology has published all the abstracts and we're just working our way through things that may be of interest to people.

Today we're going to focus on one abstract, "Germline Mutations in High Risk Prostate Cancer Patients", and I'm also going to discuss the recently published "Olaparib for Metastatic Castrate Resistant Prostate Cancer" paper, which was published on April the 28th of this year in The New England Journal of Medicine.

So this abstract, there were a number of well-known authors. Scott Eggener is one of the authors listed. It's from Chicago, Illinois. The first author was Joel Wackerbarth, and as I mentioned, the title "Germline Mutations in High Risk Prostate Cancer Patients". In the introduction, genetic testing is an integral guideline-directed component of prostate cancer care.

The author summarized their experience with the identification of germline mutations in men at a tertiary care center. In the methods, men with prostate cancer were referred for germline genetic testing from their urologist, oncologist, albeit a high-risk multidisciplinary clinic based on the following: one, the presence of metastatic disease, two, a strong family history of any prostate, breast, ovarian, or pancreatic cancer, or three, high-grade Gleason 8 or greater, in other words, Grade group four prostate cancer.

The authors performed a retrospective review of risk category, patient, and family history. Germline mutation frequency was compared among the various groups using the chi-squared methods.

Germline testing was performed in 282 men and Gleason greater than 8 was present in 171 or 60%. Metastatic disease was present in 62 patients or 22%, and family history of any PP, PB, OB, or pancreatic, breast, ovarian, etc cancer was in 194 patients or 69%. Pathogenic mutations were identified in 54 or 19% of the patients.

There was no difference in mean age between men with and without a mutation, 63.4 years versus 62.3 years. Mutation rates were similar between men with metastases at diagnosis and those without, 16 versus 20%, and again no significance. BRCA2 was the most common mutation in 27 men, or 50%, followed by BRCA1 in 11%, CHEK2‚Äč in 11%, and ATM in 7%. Ashkenazi Jewish heritage was present in 12% of the cohort and was associated with a higher mutation rate, 43% versus 16%, which was significant at a p-value of 0.001. Men with a family history of a first-degree, second-degree, or third-degree, or no family history, relatives with any POB cancer had mutations in 10, 20, 24, and 32% respectively that was significant.

So the conclusions that the authors drew were that among men with prostate cancer and the clinical indication for germline testing, the pathogenic mutation rate was 19%. Family history was associated with the presence of a germline mutation, while stage at diagnosis was not. Higher mutation rates were observed in men with Ashkenazi Jewish heritage, or family members with the history of any prostate, breast, ovarian or pancreatic cancer, both of which could be considered for genetic testing, inclusion criteria in resource-limited settings.

So this is a very interesting paper. It doesn't answer all the questions. One of the things that struck me was, did the men who were included in this abstract, did they have to have one, two, or three of the criteria that were used? And apart from that, it does highlight the role that genetic testing is going to play going forward and is currently playing.

And with that said, I feel that this is an area that all urologists who deal with malignancy need to be very familiar with. It is going to expand. It certainly is in our area and we need to be aware when we see these kinds of patients that there may well be a germline mutation which could result in saving the lives of other family members. This was a very good abstract and we will await the paper.

So it was fortuitous that The New England Journal article by J De Bono at Isle and was published roughly around the same time as we're actually doing this presentation and this was an article dealing with metastatic castrate-resistant prostate cancer and was entitled "Olaparib for Metastatic Castrate Resistant Prostate Cancer".

In terms of the background, multiple loss of function alterations in genes that are involved in DNA repair including homologous recombination repair are associated with response to PARP inhibition in patients with prostate and other cancers.

Now, PARP stands for poly adenosine diphosphate-ribose polymerase. In terms of the methods, the authors conducted a randomized open-label Phase III trial, evaluating the PARP inhibitor olaparib in men with metastatic castrate-resistant prostate cancer who had disease progression while receiving a new hormonal agent, for example, enzalutamide or abiraterone.

All the men had a qualifying alteration in pre-specified genes with a direct or indirect role in homologous recombination repair. Cohort A was 245 patients and these patients had at least one alteration in BRCA1, BRCA2, or ATM. Cohort B comprised of 142 patients who had alterations in any of the 12 other pre-specified genes, prospectively and centrally determined from tumor tissue.

Patients were randomly assigned in a 2:1 ratio to receive olaparib or the physician's choice of enzalutamide or abiraterone, which was the control group. The primary endpoint was imaging-based progression-free survival in Cohort A, according to blinded independent central review.

Let's move to the results. In Cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group with a median of 7.4 months versus 3.6 months. The hazard ratio for progression or death was 0.34 with a 95% confidence interval or 0.25 to 0.47 for a p-value of less than 0.001.

A significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in Cohort A was 18.5 months in the olaparib group and 15.1 months in the control group. Eighty-one percent of the patients in the control group who had progression crossed over to receive olaparib.

A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population, which means Cohorts A and B combined. Anemia and nausea were the main toxic effects in patients who received olaparib.

The authors conclude that in men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported endpoints than either enzalutamide or abiraterone.

Now, this was, as I mentioned, a prospective randomized open-label Phase III trial, and the authors point out that tumors and in up to 30% of patients harbor deleterious aberrations in genes involved in repairing DNA damage.

I think this is a very important trial. I think it demonstrates the use of PARP inhibitors and I think we're going to see a lot more trials and a lot more agents in this space. In fact, we know there are a number of other agents that are currently undergoing Phase III testing.

I think we should keep our eye on this space because it is a new area of treatment for these patients and it does define a high-risk group who in the past may have been missed because we did not have the use of these mutations in both germline and somatic genes and there are differences between the two. And again, that's a story for another time as to who should and shouldn't get germline versus somatic mutation or should we do everything. I don't think it will be possible to do everything certainly not at the present time, but we need guidelines on this.

Thanks for listening. This is Tom Keane coming to you from UroToday.