Experts Discuss PARP Inhibition in Prostate and Ovarian Cancers

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These interviews have been edited lightly for clarity.

Bradley Monk, MD, FACOG, FACS on PARP Inhibitors in Ovarian Cancer Treatment

Monk is a clinician at Arizona Oncology, professor at the University of Arizona and Creighton University in Phoenix, head of the US Oncology Gynecologic Research Committee, and current co-director for the Gynecologic Oncology Group Research Consortium.

Can you discuss the current approved indications for PARP inhibitors in ovarian cancer?

Poly (ADP-ribose) polymerase, or PARP, inhibitors are oral anti-cancer therapies. They’re approved in 4 tumor types—breast, there are 2 of them; pancreatic; and then in prostate, there are also 2 of them. And in those breast, pancreatic and prostate, there are molecularly defined populations. I’d like to talk to you about the ovarian cancer indications.

We have 9 PARP inhibitor indications in ovarian cancer. I can kind of put them into groups. The first PARP approved in treatment, that first group, was called olaparib, in December 2014. So we’ve been using PARP inhibitors in the clinic for 6 years. And olaparib was an accelerated approval, as were the others: rucaparib, and also niraparib; again, in the treatment setting of later lines of therapy. They’re all molecularly defined populations. Olaparib is germline BRCA mutation, rucaparib is germline and somatic mutation, and niraparib is BRCA mutation or homologous recombination repair-deficient, platinum-sensitive cancer; so patients who have a platinum-sensitive relapse that have the molecular signature, which we abbreviate HRD.

How has the reimbursement landscape for PARP in inhibitors evolved since the first one was approved? Do patients have any access issues that are driven by reimbursement decisions?

Reimbursement for PARP inhibition has been universal in the United States and even in Europe. These new frontline PARP inhibitor indications of PRIMA [trial] and the PAOLA-1 [trial]—PRIMA niraparib alone, PAOLA-1 bevacizumab, and olaparib—have now been approved in Europe. Europe is trafficking through reimbursement, but in the United States they are universally paid for. The only caveat is that in the bevacizumab-olaparib combination, there is a companion diagnostic, so generally reimbursement is only for those patients who have the molecular HRD signature.

Even though PARP inhibitors have been paid for through insurances, which is universally true, there are still co-pays, and co-pays are the real financial burden. The companies try to support through copay assistance programs—they have foundations—but there still is a substantial financial burden to these expensive oral medications. Someday there’ll be generic, and we already have multiple biosimilars for bevacizumab, and we’re seeing the prices come down. So, in the end, it’s all about value. And the value of PARP inhibitors, obviously, is the most in patients with a BRCA mutation—either germline or somatic, it’s about the same—but also a lot of value in the HRD, BRCA-like gene subset. The value in the patients that are what we call homologous recombination proficient is not as much, but they’re still approved, and certainly there is a value issue with bevacizumab. And when you add bevacizumab and Olaparib together, then obviously 2 medications are more expensive than 1.

In your experience, who are the patients who fare best with PARP inhibitors for ovarian cancer?

The fi rst randomized trials to show efficacy of PARP inhibitors were these 3 maintenance treatments in recurrent ovarian cancer, and olaparib has 2 studies, Study 19 and SOLO2; niraparib has one, NOVA; and then rucaparib has 1, ARIEL3. You can now use PARP inhibitors in treatment in recurrent ovarian cancer based on level I randomized trial data, if the patient responds to platinum, across all biomarker subgroups, because response to platinum in the recurrent setting is the biomarker. So again, if you treat a patient in platinum-sensitive relapse with carboplatin-paclitaxel, or carboplatin-liposomal doxorubicin, or even carboplatin-gemcitabine, if she responds, you can keep her in response with either olaparib, rucaparib, or niraparib without sort of ruining the patient experience. All of those studies have no decrement in patient reported outcomes, and no new safety signals identified.

What have been some key developments in the regulatory landscape of PARP inhibitors since they were first approved in ovarian cancer in 2014?

The most recent advancement in PARP inhibitors has been the use of PARP inhibitors in frontline, newly diagnosed advanced ovarian cancer. The first really amazing study was SOLO1, published in the New England Journal of Medicine.¹ The first author is Kathleen Moore. And that showed in maintenance frontline therapy—again, now in the molecularly defined population of BRCA only—had a dramatic improvement in progression-free survival. And we’re hoping that someday, frontline, PARP inhibition in newly diagnosed advanced ovarian cancer in BRCA patients will improve overall survival.

SOLO1 was a practice-changing, licensing-enabling, reimbursement sort of definitive trial, but only in patients with BRCA-mutated, newly diagnosed advanced ovarian cancer that responded to chemotherapy. The challenge, though, was it was in a very well-defined but small patient population, those that had somatic or germline BRCA mutations. So somatic mutations, tumor tests, maybe 5% to 10%; in germline, maybe 15% to 20%. So, it was only about a quarter of the patients. So then what happened is we launched this international collaboration to go beyond patients with a BRCA mutation. And there is a molecular signature that I’ve sort of alluded to, homologous recombination repair deficiency [HRD], which can be ordered either through Foundation Medicine or through Myriad, which identifies BRCA-like genes where there might be a broader opportunity for PARP inhibition.

We launched that study collaborating with the GOG [Gynecologic Oncology Group] in the European Network, and we showed that we could utilize PARP inhibitors beyond BRCA, this time, niraparib in a study called PRIMA published in the New England Journal of Medicine in December of 2019.² [It was] FDA approved on April 29, 2020, beyond BRCA. In fact, it works so well that the FDA said not only can you use it in BRCA, but BRCA-like genes, and HRD. You can use it in all comers. And the study personalized the dose, and niraparib is the only once-daily PARP inhibitor, so a very distinguishing quality. Beyond BRCA, all comers, once daily, and a personalized dose.

REFERENCES

1. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858

2. González-Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962

Neeraj Agarwal, MD, Discusses PARP Inhibition in Prostate Cancer

Agarwal is a professor of medicine, physician, and director of the Genitourinary Oncology Program at the University of Utah’s Huntsman Cancer Institute.

In your opinion, who is an appropriate candidate for a PARP inhibitor in prostate cancer?

Everyone who has a DNA repair gene defect, or homologous recombination repair defect, is a candidate for treatment with a PARP inhibitor. If we don’t identify these patients, we are offering them the alternate treatment, which is chemotherapy. And we know from multiple data sets, larger real world data sets such as flat RM, for example, the real-world use of chemotherapy is very low in patients with metastatic castrate-resistant prostate cancer, which basically tells us that our patients in the real world are not really eligible or enthusiastic about receiving chemotherapy in castrate-resistant prostate cancer. How to make them eligible and to maximize eligibility for treatment with PARP inhibitors is the most important question, which can only be answered by testing all our patients to look for these mutations.

What knowledge gaps remain in genomic testing and biomarker development in prostate cancer?

The biggest issue here is patients not being tested for biomarkers. So before we talk about what knowledge gaps there are in genomic testing, I think we need to test all patients first, and then talk about the gaps. As we know, olaparib and rucaparib are 2 PARP inhibitors currently approved for patients with advanced prostate cancer. Olaparib is approved for patients who are progressing on novel hormonal therapies, and rucaparib was approved for patients who are progressing on novel hormonal therapies and chemotherapy. So, any patient with those eligible mutations is eligible for treatment with PARP inhibitors. But how many patients are actually being tested for those mutations?

The answer is, we do not know yet, because the drugs just got approved. But based on the data, we have, less than half of the patients are being tested. In fact, in the PROfound trial, which led to approval of olaparib, 30% of patients were not even eligible to screen for the trial because tissue was not available for testing. I think the biggest gap here is we need to test these patients the first time we see them in the clinic. When we order CT scans, we order bone scans, and order laboratory data, I think we should order comprehensive genomic profiling of the tumor. And depending upon the resources, refer to the high-risk genetics clinic or germline testing at the same time for all patients with prostate cancer. I think that’s a first barrier I see before we identify more gaps.

And the second knowledge gaps are why patients do not respond in similar fashion. Why is response to PARP inhibitors in patients with prostate cancer with BRCA1 mutation, for example, not as robust as we see in patients with ovarian cancer who have BRCA1 mutation? Why for BRCA2 mutation, do we have differential responses for patients who have heterozygosity for BRCA1 loss versus homozygosity for BRCA2 loss? I think there are a lot of questions which can be answered. But the first step would be to test all these patients, so that we know at least what is going on in the majority of the patients. And not only to answer these scientific questions, but also to make these oral pills which are so much more tolerated than contemporary chemotherapy, which are the other options in the study. Testing the patients is the biggest gap we have, and we need to test everyone we see them on the first or second time.

There is discussion of giving PARP inhibitors earlier in the course of treatment. What are your thoughts on this issue?

As far as] moving PARP inhibitors from the late metastatic castrate-resistant prostate cancer setting to early on, there are 3 trials going on, which are testing PARP inhibitors in first-line metastatic CRPC setting. Right now, PARP inhibitors are approved for after patients have been treated with novel hormonal therapy in metastatic castrate-resistant prostate cancer, for olaparib and a novel hormonal therapy plus chemotherapy with docetaxel for rucaparib.

There are 3 trials which are going on including the TALAPRO-2 trial, MAGNITUDE trial, and the PROPEL trial. They are asking the question of whether PARP inhibitors may have a role in patients who are newly diagnosed with castrate-resistant prostate cancer. Another trial has started in metastatic castration-sensitive prostate cancer—so again, moving the PARP inhibitors to more upfront settings in newly diagnosed patients with metastatic castration-sensitive prostate cancer. A trial has recently started known as the AMPLITUDE trial. And in that trial, hundreds of patients who are candidates for this trial, meaning they have to have DNA repair, gene-related defects in the cancer cells, will be randomized to abiraterone plus androgen deprivation therapy versus abiraterone plus androgen deprivation therapy plus niraparib. This trial is just open to accrual in the metastatic castration-sensitive prostate cancer, and the only way to move these agents to upfront settings is to accrue on the trial. Awareness among the patients is very important, and the onus is on us now to recruit patients on these trials so that we can get results fast enough to make these drugs available for our patients early on.

PARP inhibitors are being studied in combination with other therapies—which regimens being studied do you believe hold the most promise in prostate cancer?

I think the combination of PARP inhibitors with novel hormonal therapy definitely has promise. Whether it’s a combination of talazoparib with enzalutamide as being tested in TALAPRO-2 trial, or niraparib with abiraterone in the MAGNITUDE trial, and then olaparib with abiraterone in the PROPEL trial, I think all of these combinations have promise. Also, the AMPLITUDE trial, as I said early on, for patients with metastatic castrate-sensitive prostate cancer, is a combination of abiraterone with niraparib that has promise, too. As a class, PARP inhibitors with novel hormonal therapy have a lot of scientific rationale. There is another clinical trial going on, the KEYLYNK trial, where olaparib is being tested in combination with pembrolizumab, which is an immune checkpoint inhibitor, in late metastatic castrate-resistant prostate cancer. I think that combination is also promising. Ultimately, the data will tell us whether these combinations are going to be approved or not, within next 1, 2, or 3 years. So we’re really looking forward to the results of those trials.