Dr. Oliver Sartor on Rucaparib & Olaparib.

[pjoshea13]

[1] Video interview with Dr. Sartor is 12+ mins.

He refers to two FDA PARP inhibitor approvals for PCa, from May 2020.

[2] Olaparib [Lynparza]

Wikipedia [2a]. FDA notice [2b].

Darryl reported this in May [2c] - received no response.

Approval based on the PROfound trial. NEJM paper (April) - Johann de Bono. [2d]

[3] Rucaparib [Rubraca]

Wikipedia [3a]. FDA notice [3b].

Approval based on the TRITON2 trial. [3c]

***

Useful to skim the background material before hearing the interview.

For those unfamiliar with the terms, germline mutations are those we are born with, whereas somatic mutations are acquired by tumor cells. Sartor also mentions non-mutations - genes silenced epigenetically, e.g. via methylation (a favorite topic of mine).

-Patrick

[1] practiceupdate.com/content/...

(transcript below)

PracticeUpdate: Could you give us an overview of PARP inhibitors currently being used in prostate cancer?

Dr. Sartor: In May 2020, there were two FDA approvals in prostate cancer that are particularly notable. The first was for a PARP inhibitor called rucaparib, and the second, very shortly thereafter, was for olaparib. These are PARP inhibitors that are approved in other disease states, for instance, ovarian cancer, but their application in prostate cancer was new and somewhat unique. First of all, this was a biomarker-driven approach, but the biomarker that was accepted by the FDA included a germline BRCA pathogenic alteration. “Germline” refers to the DNA you're born with. It is interesting that they chose to give FDA approval for BRCA mutated, BRCA1 or BRCA2, germline, for both rucaparib and olaparib. In addition, there were approvals in the somatic mutational setting, and this is tumor genetics, that would include BRCA1 and BRCA2 for the rucaparib but a whole variety of genes for the olaparib.

Let me discuss briefly how the FDA approvals came to be and some of the key data sets. For the rucaparib, it's fairly simple but unprecedented in prostate cancer, that the biomarker (germline or somatic BRCA1 or BRCA2) had to be positive. Then the response rate was assessed in those patients who were post-chemotherapy, post-docetaxel, and post-novel hormonal agents, such as abiraterone or enzalutamide. The response rate was impressive, with objective responses in the 40+% range, and that was sufficient for the FDA to act.

PracticeUpdate: What data led to the approval of olaparib?

Dr. Sartor: For olaparib, the approval came on the heels of the report of the PROfound study. This study did not require chemotherapy but did require use of a novel hormone, either in the hormone-sensitive or castration-resistant space. All the patients, in essence, were pretreated with abiraterone and enzalutamide, and they may or may not have been pretreated for docetaxel. The patients included not only BRCA1 and BRCA2, but in a “cohort A” also included patients with a deleterious mutation in ATM. In “cohort B,” there were a wide variety of less common alterations, such as RAD51B, PALB2, RAD54L, CDK12, and more.

In the cohort A analysis, which was prespecified, there was unequivocal improvement in the radiographic progression-free survival as compared with either abiraterone or enzalutamide, the choice of which was determined by the physician, based on their prior treatments. All patients had been pretreated with one of the others, so this was kind of a second-line, novel hormonal agent. In some cases, it was third-line, because they had already received both. Nevertheless, the docetaxel was an option and a stratification variable in the PROfound study but not a requirement.

Moving forward, the rPFS (radiographic progression-free survival) was unequivocally positive as a primary endpoint. Now, interestingly, the crossover design allowed for patients in the control arm to be treated with olaparib…if they had radiographically progressed and met other entry criteria. Despite the crossover, there was a very strong trend toward survival, but it did actually not meet the primary survival endpoint.

PracticeUpdate: Did later data clarify the picture?

Dr. Sartor: After the New England Journal of Medicine report for the PROfound trial, which was published at the end of April 2020, there was a press release on a subsequent survival analysis. This stated that the overall survival endpoint was met with olaparib in the cohort A patients, which included mutations of BRCA1, BRCA2, and ATM, despite the crossover that had occurred in over 60% of the patients. The complex issue here is [which] individual mutations were active. We have clear data in the BRCA2 subset, those with pathogenic alterations present within the tumor for BRCA2, that gene analysis in and of itself was positive on the rPFS. BRACA1 is less common, so the confidence intervals were large, but the FDA didn't worry about the individual BRCA1 subset and are willing to include BRCA1 or BRCA2.

PracticeUpdate: What about the other genes?

Dr. Sartor: The ATM subset, when analyzed in a primary analysis, did not meet positivity for rPFS. But the docetaxel pretreated subset showed a very favorable trend on the rPFS for the patients with ATM mutation being treated with olaparib. Other gene [mutations] that looked positive from cohort B…included PALB2, RAD54L, and RAD51B. But it's very difficult to achieve statistical significance with just a handful of patients. Nevertheless, I think the PALB2 story is one that we've seen across other PARP inhibitors. For many of the other mutations, we really need more data.

PracticeUpdate: How should the practicing clinician view these developments?

Dr. Sartor: The bottom line is that two new PARP inhibitors have been approved. One of these is rucaparib for BRCA1 and BRCA2 of the germline or somatic mutational state. The second is olaparib, which is approved for a variety of genes, but the BRCA genes drove the analysis, and ATM was more variable. I should mention that the CDK12 really did not seem to benefit, so I was surprised to see that the FDA put that in the basket of gene alterations that would be included in the olaparib approval. But taken together, this is very important: new precision medicine, new justification for the testing of tumors, a new inactive agent, a new class of agents in prostate cancer, and overall survival benefit within cohort A of the PROfound study, which included BRCA1, BRCA2, and ATM as an aggregated group of pathogenic alterations. This is important news, all approved in May 2020, with the New England Journal of Medicine article to boot, on the olaparib PROfound study.

PracticeUpdate: For which mutations would you definitely consider PARP inhibitors?

Dr. Sartor: In terms of the individual mutations that I have confidence in, with regard to the use of these PARP inhibitors, I think the very best evidence is with BRCA2. I think that there is a body of evidence, when taken in totality, that would support BRCA1. I might say that we don't always know when there's biallelic change and nonbiallelic change, and protein assessments were not done as part of the biomarkers; it was a genomic analysis with next-gen sequencing. In order to create the synthetic lethality that is required for the activity of the PARP compounds, you require a biallelic change and loss of protein—or, I should say, a loss of protein, because you can lose protein expression by non-genomically sequencing detected variables. This would include things like methylation.

When we look at the data beyond BRCA1 and BRCA2, I think we have fairly solid data with the totality of information from a variety of trials concerning PALB2. Beyond BRCA1, BRCA2, and PALB2, even though there's supportive data for RAD54L and RAD51B, I think we become more speculative. For things like CDK12, in truth, we just don't have much data to support the concept of activity in PARP inhibitors. For the rare mutations, we just don't have a lot of data, and I personally think that clinical trials should be done with these rare mutations to better define the response rate. In conclusion, BRCA1, BRCA2, and PALB2 are the ones that I have the most confidence in. There are others, including CDK12 and ATM, that I don't have a lot of confidence in. The rest of these rare mutations, I think we just need to study more.

PracticeUpdate: Finally, what are the toxicity profiles of these agents?

The data to date with both rucaparib and olaparib would indicate that toxicity is consistent with that of other disease states. You’d have to be quite cautious with anemia, and, of course, many patients with prostate cancer already have anemia. They have low testosterone, which predisposes to a relatively anemic state. So, anemia is definitely a concern with these agents. Other elements of myelosuppression, potentially, such as neutropenia and thrombocytopenia, are also present but relatively unusual. There can also be GI side effects. GI side effects include nausea; rarely, vomiting; and potentially, changes in appetite. I think if you follow these patients closely and particularly watch the hematologic parameters, you're going to turn out fine. But you do need to monitor the toxicity and definitely need to monitor the CBCs to be able to look for anemia, which can have deleterious effects, particularly in this elderly population.

***

[2a] en.wikipedia.org/wiki/Olaparib

[2b] fda.gov/drugs/drug-approval...

[2c] healthunlocked.com/advanced...

[2d] pubmed.ncbi.nlm.nih.gov/323...

[2e] full text: sci-hub.tw/10.1056/NEJMoa19...

[3a] en.wikipedia.org/wiki/Rucap...

[3b] fda.gov/drugs/fda-grants-ac...

[3c] pubmed.ncbi.nlm.nih.gov/320...

[3d] full text: sci-hub.tw/10.1158/1078-043...