In 2018, we saw the first approval for an inhibitor of the poly-ADP ribose polymerase (PARP) inhibitor olaparib for the treatment of breast cancer. Specifically, the approval came for patients with metastatic, HER2-negative breast cancer that harbors a germline BRCA1/2 mutation, which is an important marker in cancer because it can help women know if they’re at a significantly increased risk for breast and ovarian cancer (Angelina Jolie famously had a preventative mastectomy when she found out she was BRCA positive).
But the approval in breast cancer marked the first time that BRCA status could be used to predict which patients should receive a specific treatment in this tumor space.
The approval of olaparib in breast cancer was based on findings from the phase 3 OlympiAD study, which debuted at ASCO 2017 and was subsequently published in the New England Journal of Medicine. It’s important to remember, however, that olaparib isn’t the only PARP inhibitor on the block. In the US, there are no less than 5 main competitors with drugs approved or in development in the space:
- Pfizer’s talazoparib
- Tesaro’s niraparib
- AstraZeneca’s olaparib
- Clovis Oncology’s rucaparib
- AbbVie’s veliparib
You’ll notice I have ordered them in a peculiar way. Rather than the order in which they were approved, I have lined these agents up from most PARP “trapping” ability to lowest. You see, PARP inhibitors work both by stopping the general enzymatic activity of PARP itself, but they can also force the PARP to stay bound to damaged DNA, which is thought to increase the drug’s potential to kill cancer cells.
Pfizer’s PARP inhibitor and AbbVie’s veliparib are the only two PARP inhibitors that, at the time of writing, have not been approved for any indication. However, Pfizer is looking to change that, as the FDA accepted a new drug application for talazoparib in BRCA-mutant breast cancer, similar to what we’ve seen with olaparib already. The action date for this review is set for December 2018.
Now, we have the publication for the phase 3 EMBRACA study, released in the New England Journal of Medicine. And I thought it would be interesting to take a look and see how this study compares and contrasts with the OlympiAD study from last year.
Beginning comparisons, talazoparib vs olaparib: It starts with the patients
Now, as I wrote previously, we need to be careful with any cross-trial comparisons we make for different drugs. The conditions under which these studies were conducted can vary in subtle, but important ways. For example, even though both of these trials looked at patients with HER2-negative breast cancer with PARP inhibitors, EMBRACA allowed patients with “locally advanced” (disease that hasn’t metastasized but cannot be removed effectively through surgery in most cases) disease.
This kind of distinction can have a big implication for the results you get. Therefore, any beginning of a cross-trial comparison needs to begin by looking at the patients who joined the study. Here is a breakdown of some key patient information from OlympiAD and EMBRACA:
Now, for the most part you’ll notice that there isn’t a lot that’s different here. EMBRACA had more patients, for sure, and the median age of the placebo patients in that study may have been a bit older. But there are a few key points to focus on. First, the proportion of patients with ECOG PS 1 (this is a scale of general patient health, where 0 means there are no restrictions on physical activity, and PS1 means there is some limitation when it comes to strenuous activity) is higher in the EMBRACA study, indicating that there was a larger number of patients who are less healthy than in OlympiAD. EMBRACA also allowed patients to enroll if they had ECOG PS 2, but these patients were few and far between.
Also, EMBRACA included a small cohort of patients who had 3 or more prior lines of therapy, which you might consider as “heavily pretreated.” In many cases, patients who reach this point are in a lot of trouble, as they are quickly running out of effective treatment options for their cancer.
So overall it looks as though EMBRACA has an edge when it comes to less healthy, more heavily pretreated patients. But do note that there is an imbalance in the number of patients with hormone receptor-positive breast cancer and triple-negative breast cancer, whereas this was well balanced in OlympiAD. In general, patients with hormone receptor-positive breast cancer will fare better, since they have a larger variety of treatment options, now including advanced hormone therapies and CDK4/6 inhibitors. So this may help to explain some of the differences we’ll see later.
Key efficacy differences, olaparib vs talazoparib
With what we know so far from these two trials, two efficacy endpoints will prevail for now. First, the objective response rate, which included the following:
- OlympiAD – olaparib, 59.9%
- OlympiAD – control, 28.8%
- EMBRACA – talazoparib, 62.8%
- EMBRACA – control, 27.2%
Overall, there was no big difference here. Both talazoparib and olaparib represent a clear improvement over control in both studies, and neither seems obviously better than the other. So in general, the theoretical difference due to PARP trapping did not lead to any meaningful difference in terms of responses to therapies.
But the main goal of the both studies was progression-free survival, and for olaparib vs control, this figure was 7.0 and 4.2 months. For talazoparib vs control, PFS was 8.6 vs 5.6 months. Now, you might sit back and say “8.6 vs 7.0 looks like an improvement to me!” But this is the point where we want to be very cautious about the cross-trial comparison.
Notice, for example, that the control arm in EMBRACA (PFS 5.6 months) seems to do better than the control arm in OlympiAD (PFS 4.2 months). It’s almost the same magnitude of difference, in fact, leading me to think that the patients in EMBRACA generally were better off than those in OlympiAD, which I suspect is due to the imbalance in enrollment in favor of hormone receptor-positive patients in EMBRACA, as I mentioned before.
These data do not strongly suggest to me that there is a major difference going on in terms of efficacy. Possibly, as we learn more about overall survival, something different may emerge, but the differences in the control arms, in particular, will forever obscure the results of this study, unless someone performs a “propensity analysis,” whereby they take the data from the two trials and carefully match the patients up depending on their various features to get a better read on how they performed with the study drug and control. Obviously, we cannot do that using the published data, as they are not detailed enough.
Similarly, no huge, obvious differences in terms of safety emerge to suggest that one drug is better than the other across the board. Both olaparib and talazoparib had similar rates of high-grade adverse events and patients stopping therapy due to toxicity.
If we take a closer look at the breakdown of individual adverse events, however, some differences do emerge. For example, grade 3 or higher hematologic adverse events like anemia, thrombocytopenia, and neutropenia were less common in patients receiving olaparib in the OlympiAD study:
As you can see, patients do appear to have an increased risk of anemia and neutropenia with talazoparib. However, it should be noted that the neutropenia did not increase the risk of infection in the study, so this may not be of grave concern for practicing clinicians. What is clear is that both drugs are at least somewhat better than standard therapy, which more often led to treatment discontinuation due to toxicity in both studies.
From these data, it is unclear which, if any, treatment is going to be superior in the marketplace once talazoparib gets approved. Neither presents a clear case that it is the better option across the board for BRCA-mutant breast cancer, and both seem reasonable. In certain patients who may be prone to infection, a doctor may give the edge to olaparib due to the risk of high-grade neutropenia.
Furthermore, olaparib has been on market since 2014, giving doctors more time to have gotten comfortable with prescribing it and dealing with the toxicities. This first-mover advantage may be blunted somewhat since it hasn’t been approved in breast cancer for all that long yet, though, and Pfizer may be able to take advantage of the fact that this is a nascent market. Pfizer may also have a slight edge in that their drug requires one pill a day, whereas olaparib has to be given twice daily, two pills per dose. This kind of pill burden can create an issue for patients to remain compliant, day in and day out (ever miss a dose of a prescription?), which can be bothersome for some.
We can definitely surmise that it’s going to be a competitive landscape for both companies, and I think that there will be a fair amount of room to operate, for now, or at least until other PARP inhibitors start to enter the treatment space.
Thank you for checking this short article out today! If you liked what you read, please consider checking out some other stuff on Invest Against Cancer, such as my article on how to move when you’ve picked a winner! Have a good day!
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