Agarwal Outlines Importance of Olaparib Approval in HRR-Mutant mCRPC

Neeraj Agarwal, MD

The FDA approval of olaparib (Lynparza) for adult patients with previously treated homologous recombination repair (HRR) gene—mutated metastatic castration-resistant prostate cancer (mCRPC) provides new hope for patients who did not have many effective treatment options available, according to Neeraj Agarwal, MD.

The PARP inhibitor was specifically approved for patients with deleterious or suspected deleterious germline or somatic HRR gene—mutated mCRPC who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga).

“Overall, the message is very strong: this is a very viable strategy,” said Agarwal, who served as one of the investigators on the pivotal phase 3 PROfound trial, which supported the FDA approval. “In my view, for patients with mCRPC who are harboring HRR alterations, olaparib should be the number one option—as long as they are medically fit, as determined by the investigators or the physicians, or unless they have any contraindications. I don't think there is any other choice like it.”

In the PROfound trial, treatment with olaparib led to a 66% reduction in the risk of disease progression or death versus abiraterone acetate or enzalutamide (HR, 0.34; P <.0001) in patients with BRCA1/2- or ATM-mutant mCRPC. Across the entire population of patients with HRR-mutant mCRPC, olaparib induced a 51% reduction in the risk of disease progression or death compared with the antiandrogen agents (HR, 0.49; P <.0001). Further, in the BRCA1/2- or ATM-mutated subgroup, the PARP inhibitor also significantly improved overall survival (OS; HR, 0.69; P = .0175).

“Overall, the results are really remarkable, especially with regard to the primary end point, as we saw a doubling of radiographic progression-free survival (rPFS); this is something we have not seen in the context of any other drug in this setting yet,” said Agarwal.

The regulatory decision also underscores the need to perform comprehensive genetic sequencing on all patients when they are first seen in the clinic, according to Agarwal.

“I would like to emphasize obtaining comprehensive genomic profiling of all patients with metastatic prostate cancer, regardless of whether they have castration-sensitive disease or castration-resistant disease,” said Agarwal. “Be ready with the results of genomic sequencing. We need to know which patients have tumors that are harboring HRR defects as soon as possible.”

In an interview with OncLive, Agarwal, who is also a professor of medicine, a physician, and investigator at the Huntsman Cancer Institute of the University of Utah, provided insight into olaparib, further discussed the data that led to the regulatory approval, and shared the implications of this approval in mCRPC.

OncLive: Could you start by explaining your role on the PROfound trial?

Agarwal: I was one of the members of the global steering committee of the PROfound trial. Looking back, it has been a huge privilege and honor to be involved in the approval of a treatment, a very novel therapy, for patients with mCRPC. What makes it even more special, is that [prior to rucaparib (Rubraca), which was approved very recently], it has been 7 years since we saw the last drug approved. This has been a very exciting journey.

Could you provide some background on olaparib?

Olaparib is a PARP inhibitor, and in the previous smaller trials, the agent was shown to be efficacious in patients with tumors harboring HRR defects or alterations. I'll take a minute to discuss the mechanism of PARP inhibition. As we know, millions and millions of cells in our bodies divide on a daily basis; that basically means that DNA has to uncoil to become 2 single-strand DNA and then they again replicate to become a normal double-stranded DNA. It is hard to imagine that this machinery is perfect.

During a normal process, single-strand DNA can always develop breaks and those are repaired by the PARP enzyme. Sometimes PARP is not really effective or not efficient and it leads to persistence of the breaks in the single-strand DNA. When this single-strand DNA replicates, these breaks become double-strand DNA breaks and that is where HRR comes into play. Double-strand DNA breaks are repaired by the HRR pathway; if it does not get repaired, the cell will die.

For patients whose tumors harbor the HRR defect, the most common [abnormality] is BRCA2 deficiency, but many other direct or indirect mechanisms exist to repair the homologous recombination repair pathway. Multiple direct or indirect proteins which fix the double-strand DNA. In tumors that are already deficient in the HRR pathway, meaning they are deficient in BRCA1/2 or many other proteins. If we inhibit the single-strand repair using a PARP inhibitor such as olaparib, the [cancer] cell cannot survive. This is the premise for these PARP inhibitors to be developed in the context of cancers that are harboring these HRR defects or alterations.

With regard to the PROfound trial, could you discuss the trial design and expand on the patient population included in this research?

PROfound was a multinational, multicenter phase 3 trial in which patients who had mCRPC and who had disease progression on at least 1 novel hormonal therapy, including enzalutamide or abiraterone, were randomized to treatment with olaparib versus physician’s choice of hormonal therapy, either abiraterone or enzalutamide. It should be noted that there were 2 cohorts. Cohort A had to have BRCA1/2 or ATM alterations, and cohort B had other alterations, including CHEK1/2, RAD51BCD, PALB2, and many others. The primary end point of the trial was the rPFS as determined by independent review committee in cohort A. Notable secondary end points were rPFS in the overall population and OS.

Patients were randomized in a 2:1 fashion to receive olaparib versus 1 of the other novel hormonal therapies. It should be noted that many of these patients had received docetaxel chemotherapy, as well. In fact, 65% of the patients who enrolled on the PROfound trial had received docetaxel chemotherapy, so we are talking about [patients with] a very advanced phase of mCRPC. We have very limited options out there [for this population].

What are the options? We are talking about cabazitaxel (Jevtana) chemotherapy, which is associated with a median OS benefit of less than 3 months, or some other therapies that have not really been tested in the setting when patients have progressed on [a hormonal agent] and docetaxel. Radium-223 dichloride (Xofigo) has been tested in this setting and has shown a survival benefit of 3 months in patients who did not have visceral metastasis. As such, if you look at the overall picture, there is literally nothing substantial out there to treat our patients with other than cabazitaxel or radium-223 in this setting.

What were the results of the PROfound trial?

As we know, the primary end point of rPFS was met in cohort A; the difference was basically doubling of rPFS with olaparib compared with the control, which included abiraterone or enzalutamide. The hazard ratio was 0.34, favoring olaparib, which basically translates into 66% reduction in risk of disease progression or death. This is really remarkable.

The rPFS in the overall population was also improved, again with a hazard ratio favoring olaparib at 0.49; again, this translates into a 51% reduction in the risk of progression or death. We also know that OS, which was a secondary end point of the trial, was also improved in cohort A [with olaparib]. And at the time of the report [in the New England Journal of Medicine], the OS was significantly improved, with a hazard ratio of 0.64, which again, translates into 36% reduction in the risk of death in this patient population. The OS was also improved in the overall population, with a hazard ratio of 0.67, favoring olaparib, meaning a 33% reduction in the risk of death.

In addition to rPFS and OS, we saw improvement in pain responses and objective responses. In fact, with regard to objective response, if you look at cohort A, the objective response rate (ORR) was 33% in patients who had measurable disease versus 2% patients who were on the hormonal therapies. This was really a dramatic difference in objective responses between the 2 arms.

We are seeing a consistent improvement in rPFS, OS, delaying pain, prostate-specific antigen responses, and objective responses. If you look at the subgroups, patients who had visceral metastasis, those who had de novo metastasis, all [of them] were benefitting with olaparib in a very consistent fashion.

What did the safety profile look like for the agent?

As we know, this is a class of PARP inhibitors. Anemia was dominant in the olaparib group compared with the control group; that is not surprising. Nausea was also more [commonly observed] with olaparib versus the control arm. I think because of anemia, fatigue was also more common in the olaparib arm compared with the control arm. However, if you look at the patient population, one that has such limited options, and if you look at the safety profiles of other agents that are usually used in this setting, olaparib’s safety profile was very refreshing.

Yes, adverse events (AEs) with olaparib include anemia and nausea. Our patients experience these events, but it’s not very difficult to control nausea nowadays and it’s not very difficult to manage anemia-related symptoms, either. If the anemia gets worse, we can always manage those symptoms. That being said, we did not see the [kind of] AEs that we see with maybe a second- or third-line chemotherapy. Compared with those events, [this drug is] well tolerated overall. I am hoping to see the quality of life (QOL) data in the full-length manuscript in the coming months. I [predict] that will basically reinforce what I'm thinking, meaning that the QOL was, as reported by the patients, also improved when they were treated with olaparib compared with the control.

What are the clinical implications of this approval on the treatment paradigm?

Patients with HRR defects in their tumors, especially [those with] the alterations included in the trial, are able to receive treatment with olaparib, and that's great news for our patients. If you talk about individual gene alterations, I would like to highlight the fact that these are small subgroups. We know that PARP inhibitors are not as active in [tumors harboring] ATM alterations as it is in [tumors harboring] BRCA1/2 or maybe PALB2, for example. It is tricky to do subgroup analysis of individual gene alterations because if you look at the numbers, they keep getting smaller. I would be hesitant to comment on the efficacy of olaparib in individual gene alterations just because the sample sizes were so small. Olaparib was approved for patients with mCRPC harboring certain genetic alterations—ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54LM, as well as germline BRCA1 and germline BRCA2—and who have had disease progression on a novel hormonal therapy, including abiratereone or enzalutamide. Please note that the receipt of chemotherapy in the mCRPC setting is not required [for a patient] to be eligible for treatment with olaparib. I would also like to highlight that in a pre-specified analysis, those men with ATM alterations did not benefit in the trial. Although it possible that in this subgroup, the patients in the control arm performed better than expected, thus negating the benefit seen with olaparib, I would be exclude these patients with ATM alterations for now, until I see further data to justify this.

How do you see the approval impacting the use of genetic testing?

I'd like to really highlight a particular fact about this clinical trial, which may not be discussed widely in the media and can easily be ignored when we are reading the paper or seeing the presentations. Approximately 4000 patients were screened for the availability of tissue and 70%, so 2792 patients, had tissue available for screening for genomic alterations. We lost 30% of patients to genomic screening. Of those patients who had successful screening, because of the availability of viable tissue, and who went through quality checks, 28% had qualifying mutations for this trial, including BRCA1/2, ATM, and many other mutations. What is the message here?

The number one message I'm getting from these results is, we need to sequence the tumors of these patients as soon as we see them, the first time we see them. Whether patients are coming to us with castration-sensitive metastatic prostate cancer or whether they're presenting to us with CRPC. If we do not do the genomic screening by comprehensive genomic profiling when we see them first, there are several problems. Number one, tissue may not be available. Number 2, the quality of the tissue may not remain intact to allow for successful genomic sequencing. The more recent the tumor tissue is, the more productive the gene sequencing results will be. Number 3, when patients are progressing on novel hormonal therapy and/or chemotherapy with docetaxel, the pace of disease progression is very rapid and we may not have enough time at that time [of progression] to obtain tissue for the biopsy, send it for gene sequencing, and get the results back. The whole process can easily take 4 to 6 weeks and patients may lose their performance status during this time.

Based on these 3 facts, my practice, and I highly recommend this to be practice elsewhere, is to obtain comprehensive genomic profiling of the tumors of these patients the first time we see them. At least let's start the discussion and get done with the sequencing within 2 or 3 months. Patients can receive their usual therapies, but then when the time comes for them to receive olaparib, we are not struggling to get the test results. This is the number one message I have [after] seeing the screening numbers. How many patients were really screened? Thirty percent of patients who had tissue biopsies available or had gone through quality check were harboring these HRR defects; that's a big number in our clinic.

Are any ongoing research efforts examining olaparib in other settings or in combination?

Multiple trials are ongoing, not only with olaparib, but with other PARP inhibitors, as well. The trial that comes to my mind is the one that is examining olaparib with pembrolizumab (Keytruda) versus [hormonal agents]. Olaparib is being tested in combination with abiraterone in the PROpel trial, which is a first-line mCRPC trial, so basically, the drug is moving upstream.

Many other trials are testing very similar strategies. One trial that I would like to particularly highlight in this context is the TALAPRO-2 trial, which I have the privilege of having been involved with from its inception; this trial is testing talazoparib (Talzenna) with enzalutamide versus enzalutamide. I think many of these combinations are going to be approved for use down the line. Overall, the field is evolving very fast and it's all good news for our patients.

Is there anything else that you would like to add?

This is an oral pill; it allows our patients to stay at their home. The safety profile, in my view, with this oral pill is much better than the salvage chemotherapy regimens we are using for these patients in our clinic. With the radiographic PFS with olaparib being 7.4 months, just to add 7.4 months for those patients who are progressing on enzalutamide, abiraterone, or both, is very meaningful; the majority of these patients had [also] progressed on chemotherapy.

OS results have been announced by a press release; there is a confirmed [benefit], but we do not know the numbers yet. We will see them very soon, but I think everything is headed in the right direction.

Also, it has been really easy nowadays [to perform comprehensive genomic profiling] with the availability of comprehensive genomic profiling platforms offered by multiple companies. Really, any oncologist from any part of the planet can order these tests; it doesn't require access to scientific laboratories in unique places in the world. Now, anyone can order them. Given the widespread availability of these tests, there is no reason for us to not test our patients. Test them and be ready with the results. If they have tumors harboring HRR alterations, they should have the opportunity to receive olaparib and other PARP inhibitors as they keep getting approved.

Lynparza Highlights of Prescribing Information. FDA. Updated May 19, 2020. https://bit.ly/2WLJt7u. Accessed May 19, 2020.