ASCO New Data: PARP Inhibitors

Joyce O’Shaughnessy, MD: Another really important topic in the very rapidly evolving landscape in triple-negative breast cancer germline breast cancer gene [BRCA] patients is the topic of poly [ADP-ribose] polymerase [PARP] inhibitors. There were interesting data sets at American Society of Clinical Oncology [ASCO]. Some may be perhaps immediately practice-changing, and then another one that I think is real forward looking. Tiffany, why don't you give us a summary of where we are with PARP inhibitors and your take on some of the new data.

Denise Yardley, MD:I'm happy to. I think we've all had some time to digest the data from OlympiAD and from EMBRACA that led to the FDA approvals of both olaparib and talazoparib for patients who carry germline BRCA1 or BRCA 2 mutations. Just as a reminder, the OlympiAD study was a randomized trial of olaparib versus treatment of physician's choice. This was for patients with known pathogenic germline BRCA1 or BRCA2 mutations.

In that study where the primary end point was progression-free survival, the single agent PARP inhibitor actually was associated with about a 3-month improvement in median progression free survival [PFS] over the cytotoxic chemotherapy. Actually, a lot of the quality of life and toxicity measures really favored the PARP inhibitor over cytotoxic chemotherapy. An interesting follow up in the OlympiAD data was a subset analysis of those patients treated in the first-line setting, and olaparib was associated with about a 50% improvement in median overall survival over chemotherapy of physician's choice.

If we look at the EMBRACA data that led to the talazoparib approval, EMBRACA was also a randomized phase 3 study of a single agent PARP inhibitor up against treatment of physician's choice. Very reasonable control arm chemotherapies such as capecitabine, gemcitabine, vinorelbine, and, similarly, talazoparib was associated with a significant improvement in median PFS: about a 3-month absolute difference there, and about a 40% to 50 % improvement in PFS.

We have some interesting new data; Jennifer Litton presented at American College of Radiology about the overall survival data from the EMBRACA study and there after a follow up of almost 4 years. There really was no apparent significant difference in overall survival in the overall study population for talazoparib versus standard-of-care chemotherapy, and median overall survival was about a year and a half or about 19 months. There are no overall survival data that was proven with the talazoparib agent, and we do have some data in a subset analysis for overall survival benefit from olaparib.

That's where we've been until ASCO where we had 2 really interesting presentations, both looking at the potential advantage of PARP inhibitors beyond just germline BRCA1 or BRCA2 mutations. I think that the first study that I'd like to spend some time looking at was the SWOG trial that was presented; this was a SWOG S1416. This was a randomized phase 2 trial in patients with triple negative breast cancer or known germline BRCA1 mutations, treated in the first or second line. Patients were randomized to either cisplatin monotherapy or cisplatin in combination with veliparib.

I'm making a note because we do have some other trials that have previously reported on veliparib. In this particular trial veliparib was dosed at 300 mg twice a day for a 14-day continuous regimen. This is a much higher dose than what we have seen in previous studies such as BrighTNess and BROCADE. In this trial of cisplatin versus cisplatin plus veliparib, the primary end point was PFS but in some unique subsets or specified subsets. One subset of interest was those patients with germline BRCA mutations.

A second subset of interest was those patients who had BRCA-like triple-negative breast cancer. That was defined in a number of different ways. You could have a homologous recombination deficiency [HRD] assay with a cut point of greater than 42 suggesting you have a BRCA-like cancer. You could have a somatic BRCA1 or BRCA2 mutation in the tumor to be classified in this way. You could have BRCA1 promoter methylation, and you can have germline mutations in other genes besides BRCA1 or BRCA2 that are known to have HRD deficiency regulation. That class of tumors were considered BRCA-like.

Then the last subset to be looked at were those that were non­–BRCA-like tumors. These patients in the study had no prior exposure to cisplatin or PARP inhibitors. More than 300 patients were randomized in the phase 2 study. The majority of them were really first-line patients, almost three-quarters of the patients were treated first line as opposed to second line, and when you look at the characteristics of these patients only about 13% carried a germline BRCA mutation.

About half of the patients were classified as BRCA-like, and the other half were non–BRCA-like. I think that the really big, exciting take-home message from all of these analyses of the SWOG study was that in the patients that were reclassified as BRCA-like triple-negative breast cancer, there was about a 50% improvement in PFS in those patients. The PFS increased from about 4.2 months to almost 6 months, and that was also associated with an improvement in response rate from about 30% to 45%.

This met statistical significance. They looked at overall survival for this BRCA-like subset and there was a trend towards the addition of veliparib associated with OS, but that did not meet statistical significance. When they looked at the germline BRCA mutation patients, remember that a very small subset, only 13% of the overall study population, did not appear to have an advantage to adding veliparib in that small subset.

Similarly, in the non­–BRCA-like population, there did not appear to be an advantage to veliparib over cisplatin as a single agent. It is worth noting that the addition of the PARP inhibitor to cisplatin was associated with significantly more grade 3 or 4 toxicity. This is not surprising; we’ve seen this when other PARP inhibitors have attempted to combine with platinum and other cytotoxics.

I do, however, think that this was interesting data to start to see perhaps a broader application for PARP inhibitors in triple negative breast cancer beyond the indication of just germline BRCA1 or BRCA2 mutations. There was some other interesting data. We can talk about another trial that is similar in some ways; it was the TBCRC 048 study, and Nadine Tung , MD, presented this at ASCO as well. This was a single arm olaparib monotherapy trial and a phase 2 study of about 54 patients.

The eligibility for the study were patients who had somatic BRCA1 or BRCA2 mutations, germline mutations, or other cinematic mutations that are also known to be associated with HRD. This could include mutations like ataxia-Telangiectasia mutated, checkpoint kinase 2, RAD50, P10, and BARD1. There was an extensive list of potential candidate mutations that are either somatic or germline to be eligible for the single agent olaparib arm. I will say that this was a first-, second-, or third-line study, and when the analysis was performed, the primary end point was response rate. The data was divided to look at cohort 1 based on germline mutations or cohort 2 based on the somatic mutations.

What was really compelling and exciting to see was that overall response rate was about 30% to 33%, both for cohort 1 and cohort 2. When you dive into the data a little bit more carefully and you look at those patients who had germline mutations other than BRCA1 or BRCA2, all the responses were associated with germline PALB2 mutation. When you looked at the cohort of somatic mutations, again, where the response rate was about 30%, all those partial responses were attributed to somatic BRCA mutation. This is exciting; we are starting to find other potential candidate biomarkers to suggest benefit from PARP inhibition.

The TBCRC 048 study is now expanding recruitment, and there will be additional slots available for patients with germline PALB2 mutations or somatic BRCA mutations to allow for continued exploration of single agent olaparib in that space.

Transcript edited for clairty.