1. DiGiulio, Sarah

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The FDA has recently approved two poly (ADP-ribose) polymerase (PARP) inhibitors, rucaparib and olaparib, for men with metastatic castration-resistant prostate cancer (mCRPC) and mutations in homologous recombination repair genes. That should be good news for patients with this type of cancer and for proponents of precision medicine.

Michael Schweizer, M... - Click to enlarge in new windowMichael Schweizer, MD. Michael Schweizer, MD

But in a new "Comments and Controversies" article in the Journal of Clinical Oncology, Michael Schweizer, MD, Assistant Professor in the Division of Medical Oncology at University of Washington in Seattle, poses words of caution (2020; doi: 10.1200/JCO.20.01755).


Both rucaparib and olaparib were recently approved by the FDA for treatment for patients with prostate cancer, but the former's approval is restrictive to only BRCA1- and BRCA2-mutated prostate cancer and the latter's approval is permissive of a larger number of genes directly and indirectly involved in homologous recombination repair. The approval for olaparib includes several genes that, to date, have not individually been shown to predict for response to PARP inhibition, Schweizer noted in the JCO article.


"We were surprised at the stark differences in their respective labels," Schweizer told Oncology Times. "I don't think revoking the approval is necessary; physicians just need to be judicious in how they use olaparib."


Here's what else he said about the approvals and how physicians can be more judicious in their use of the new drugs.


1 One of the issues you bring up in the editorial is that the evidence supporting the efficacy of both drugs is different. Can you explain the key differences between the evidence that led to the approval of both drugs?

"Rucaparib received accelerated approval on the basis of the non-randomized TRITON2 study. In this study, they observed low response rates in men with mutations in genes other than BRCA1/2. As such, they focused their efforts on developing rucaparib for the subgroup with BRCA1/2 mutations only.


"Olaparib was approved on the basis of the randomized Phase III PROfound study. This trial allowed patients with a long list of homologous recombination gene mutations to enroll. The primary analysis focused on those with BRCA1/2 or ATM mutations (cohort A). A second cohort (cohort B) allowed patients with mutations in other homologous recombination genes. Secondary endpoints evaluated the outcomes in the combined Cohort A and B group. Because primary and secondary endpoints were met, the FDA granted approval across almost every gene that was included in the study eligibility. PPP2R2A was not included in the label because there was a trend toward worse outcomes with olaparib treatment in these patients."


2 So what do you find problematic about the data from the olaparib study?

"PROfound was a positive study and the statistical plan laid out in the protocol was followed, so I don't think you can claim the results were misinterpreted.


"However, when you look at the data, it is fairly clear that the observed benefits were primarily driven by the group with BRCA mutations. If you focus on the patients with non-BRCA mutations, it's hard to conclude that olaparib is more effective than the control. It is likely that olaparib works well in some patients with non-BRCA mutations (such as PALB2), but it is also likely that it does not work for every gene included in its FDA label (such as CDK12).


"I generally favor broad indications since this gives physicians more latitude to use their judgment in treating patients. We just wanted to make sure that physicians understand that the benefit of olaparib in those without a BRCA mutation has not been clearly demonstrated. My concern is that drugs that have clearly demonstrated efficacy (such as docetaxel) may get overlooked in favor of olaparib, which could lead to poor patient outcomes in some cases.


"More studies are needed to understand which mutations are predictive of response to PARP inhibitors. Olaparib's broad label will likely be a barrier to completing these studies since many patients will receive this as standard of care and not be enrolled to studies designed to determine the efficacy of PARP inhibitors in non-BRCA mutated subgroups."


3 What's the bottom-line message practicing oncologists and cancer care providers should know about these drugs?

"For patients with a non-BRCA homologous recombination mutation, I would advocate that they participate in a clinical trial. If this isn't an option, it's important to critically evaluate the data supporting the use of PARP inhibitors for a given mutation. In some cases, other drugs may be a better choice. Of course, if there are no other options for an individual and olaparib is still on the table, I would certainly consider using it."