Salani Reviews Role of PARP Inhibition in Ovarian Cancer

Ritu Salani, MD, MBA

Director, Gynecologic Oncology

University of California Los Angeles

Los Angeles, CA

EVENT SUMMARY

At a live virtual event, Ritu Salani, MD, MBA, discussed multiple studies that back up the use of PARP inhibition as a first-line maintenance therapy for patients with advanced ovarian cancer. Salani discusses the highlights of these studies and how niraparib (Zejula) fits into the treatment paradigm.

Targeted Oncology^TM: What data support the use of olaparib as first-line maintenance therapy for advanced ovarian cancer?

SALANI: The SOLO-1 trial [NCT01844986] used olaparib [in the treatment arm], and the [key patient population] had BRCA mutations—mostly germline mutations—and a couple patients had somatic BRCA mutations. These patients responded to primary chemotherapy with a platinum and taxane-based regimen. Once they showed their response, whether it was partial or complete, they were [randomly assigned] to olaparib [Lynparza] or placebo. This was a 2-year end point, so those patients were on the drug for 2 years unless toxicity or progression occurred beforehand.¹

The progression-free survival [PFS] after 5 years of follow-up was revolutionary in ovarian cancer, even though we had [patients with] BRCA [mutations] who we always suspected did better. The median PFS was 56 months for olaparib vs 13.8 months for placebo [HR, 0.33; 95% CI, 0.25-0.43], a difference of over 3 years.2 This study did cap treatment at 2 years. A handful of patients went above that. We don’t know when the right time to stop is, but toxicities such as MDS [myelodysplastic syndrome] or [acute myeloid leukemia] put the 2-year cap. We’re probably not gaining a lot of benefit from keeping patients on olaparib for greater than 2 years. I’ve had patients who have hit that 2-year mark and are resistant to going off therapy because it’s working for them. I think it’s always that balance of adverse events [AEs] vs the benefit of therapy, so if they have some residual disease, it’s a bit of a different conversation, but this is reassuring data.

For the subgroup analysis, every subgroup had a benefit from the experimental arm or the olaparib arm regardless of BRCA status [BRCA1 or BRCA2] and age of the patients. Olaparib was better in all subgroups.¹ Even after 5 years of follow-up, the safety profile remained the same. We saw similar AEs, and there were no additional cases of MDS reported, which was [approximately] 1% in this population.

There was not a high rate of new primary malignancies. Remember, this was a high-risk group because of the BRCA mutation, but the safety profile was unexpected. This was a well-tolerated regimen. Dose interruptions occurred in 52% of patients on olaparib, but dose discontinuation only occurred in 12% of them, so [it was] manageable with appropriate strategies.^1,2

What data support the use of niraparib as first-line maintenance therapy for advanced ovarian cancer?

The PRIMA study [NCT02655016] used niraparib maintenance after response—either complete or partial—to frontline platinum-based chemotherapy. The patient population was all-comers, and they did assess for the HRD [homologous recombination deficiency] status. Patients were [randomly assigned] to niraparib daily vs placebo, whereas olaparib was twice daily. That is one of the differences between the drugs. They did stratify based on the tumor response, whether they received neoadjuvant therapy, and their HRD status. The treatment was continued for 3 years or until toxicity.³

These were different patient populations, however. First, you have [those who carry a] BRCA mutation, and then the high-risk cohort who had the poorest prognosis with stage IV disease, or those who had bulky disease, but they did respond to chemotherapy. In that poor prognostic starting group, niraparib was a little more favorable. Most of these patients received neoadjuvant chemotherapy.

In the overall population, the PFS was 13 months for niraparib vs 8 months for placebo [HR, 0.62; 95% CI, 0.50- 0.76; P < .001]. This included all-comers, and there was much more benefit in the HRD population, with or without BRCA, at 22 months vs 10 months [HR, 0.43; 95% CI, 0.31- 0.59; P < .001]. The overall survival [OS] at 24 months was 84% with the niraparib vs 77% with placebo [HR, 0.70; 95% CI, 0.44-1.11]. So impressive data with niraparib, as well.³

How does the subgroup analysis in this study impact the use of treatment?

There were [patients who carried a] BRCA mutation [and] who harbored HRD pathway mutation, and then the BRCA wild type. The HRD status was a good predictor. Both sets of these patients had nice responses. The hazard ratio was a little improved in [those who carried the] BRCA mutation, at 0.4 vs 0.5 for the BRCA wild type, so [there was] a nice clinical benefit in the HRD subgroups regardless of the BRCA mutation status.

The homologous recombination–proficient [HRP] group— who I think [are] now referred to as HRD test negative, because we don’t know [whether] they’re truly deficient, just that the test didn’t pick it up—still had a benefit with niraparib. [However], it was less pronounced, with a median PFS of 8.1 months vs 5.4 months. The hazard ratio was statistically significant at 0.68. Niraparib got FDA approval in all-comers because of these differences. The benefit was a little less substantial—still, a benefit was seen.³

For the subgroup analysis, once again, the benefit was pretty much across the board.³ This was a bit of a different population, so not as clear-cut as in olaparib, but pretty much in all subgroups, everything leans toward the niraparib. So it is something I think has changed practice, and hopefully will continue to change practice.

The interim analysis of OS has not yet reached maturity, and the OS event rates are low. In the HRD population, the overall population alive at 2 years was 91% vs 85%, respectively, but in the HRP population, it was 81% vs 60%. So a little bit of a more stark contrast, but these are preliminary data, so I want to see [these] mature more.⁴ But I always like these numbers, because this might be one of those few chances these patients have to use a PARP inhibitor, and we don’t know [whether] they might be platinum resistant or they may not be able to tolerate it, so I think this is something to always keep at the back of your mind, especially in the HRP population.

There were, once again, no new safety signals seen. There were higher rates of myelosuppression, anemia, thrombocytopenia, and neutropenia with niraparib. One patient was diagnosed with MDS after 9 months of treatment, but most of these AEs were reversible and manageable with dose reductions or dose interruptions. The discontinuation rate with niraparib was a little higher because [of the] higher-risk population, but it was still pretty manageable. It was [approximately] 20%, so [it was] still a very manageable regimen.³

Do you offer niraparib to patients who are HR negative or HRP?

I do offer it to my patients, and I have that same discussion about the benefit. For my [patients who are] HRD and [have a] BRCA mutation, I don’t even make it a discussion because this is standard treatment. But for [those who are] HRP, I do discuss it. I tell them there is some benefit, but it is limited. Often, I’ll have patients who may start it, and I might have patients who say they don’t want to deal with it—they’re done with chemotherapy, tired, and don’t want to do it—and I think that’s OK. I also have patients who might try it and then don’t have tolerance for AEs, so they may stop it more for toxicities or tolerance. But I do offer it to all my patients.

We need to find better therapies for these patients. If it’s not PARP inhibitors in this space, maybe there’s going to be something we can use. We’re not going to talk about it today, but there’s another trial of rucaparib [Rubraca], called ATHENA [NCT03522246], looking at frontline maintenance with rucaparib, but they also have arms of immunotherapy in there, and we haven’t seen immunotherapy be successful in ovarian cancer.

There are other trials looking at combinations of PARP inhibitors, immunotherapy, and bevacizumab [Avastin], so hopefully we’ll find something. There are [also] some novel strategies that are coming out, [such as] the vaccine trial [Gemogenovatucel-T (Vigil)] that’s looking at the HRP population. So, we’re looking at different ways of exploring that HRP population. They still have a high rate of recurrence, so if niraparib can help blunt that, I’m all about that. But you’re right, it’s not as easy, and that’s the only FDA-approved PARP inhibitor we have in that space right now.

What’s the approximate incidence of HRD in these patients?

When you look at the breakdown of patients with ovarian cancer, [approximately] 20% to 25% will have a true BRCA mutation. [Approximately] another 30% to 35% will have an HRD pathway mutation, so [approximately] 50% of patients are going to be HRP.

What data support the use of olaparib plus bevacizumab as first-line maintenance therapy for advanced ovarian cancer?

The PAOLA-1 trial [NCT02477644], once again, had patients with advanced ovarian cancer. They had to have a partial or complete response to platinum-based chemotherapy, and they had to receive bevacizumab with chemotherapy. Once they completed their 6 cycles, they either received olaparib and bevacizumab or bevacizumab and placebo alone. In this study, they took all-comers. Olaparib plus bevacizumab did have a PFS benefit over bevacizumab alone. The OS data are not mature.⁵

So, including [those who carry a] BRCA mutation, the HRD-positive group had the most significant benefit, with the hazard ratio of 0.33, so a median PFS of 37 months vs 17 months. In [those who are] HRD positive, excluding the BRCA mutation, we still saw a very significant benefit in PFS of 28 months vs 17 months, with a hazard ratio of 0.43. In the HRD-negative group, or those [who] did not have known testing status, we didn’t see a benefit, and the hazard ratio was 0.92, which was not statistically significant.⁵

The FDA approved this combination for [those who are] HRD positive [with a] BRCA mutation but not [for those who are] HRD negative, because there was no known benefit over bevacizumab alone. Many of us wish there was an olaparib-only arm, [but] we just don’t have that information. [Whether] bevacizumab adds anything is always going to be a question we just can’t answer. [However], if you use bevacizumab as part of your chemotherapy strategy, adding olaparib for [patients who are] HRD or [those with a] BRCA mutation is a very viable option.

Some will argue for switched maintenance therapy, meaning stopping the bevacizumab, then just putting them on a PARP inhibitor afterward, depending on the therapy. I think you have different strategies, and it can be personal. The subgroup analysis showed most subgroups pretty much leaned toward olaparib plus bevacizumab, except for in the HRD-negative or unknown groups.⁵

Not surprisingly, we saw a little bit of higher AEs in the placebo arm because they had bevacizumab with it, but this was generally a very well-tolerated regimen. There were 54% with dose interruptions and, once again, [approximately] 20% of patients had to discontinue, so [approximately] 80% of patients were able to continue therapy until progression or they stopped, but not because of AEs. We know hypertension is associated with bevacizumab, and you can see the rates of hypertension were higher in the bevacizumab and placebo arm than in the olaparib and bevacizumab arm, so something interesting about that AE. Otherwise, expect it as you give either the monotherapy or combination.

What supports the individualized niraparib starting dose based on baseline body weight and platelet count?

With niraparib, they first found that the 300-mg once daily dosing was being dose reduced in most patients. If you look at the NOVA trial [NCT01847274], which is a second-line therapy trial, [approximately] 60% of patients required a dose reduction, which is high, so they looked at the stratification of body weight using 77 kg or less and 150,000 platelets or less. They said, “Maybe we should start those patients at 200-mg once daily dosing as opposed to 300 mg.” So we affectionately call this 'weights and plates' as a nickname.

Patients who met the criteria of less than 77 kg or less than 150,000 platelets when they started at 200 mg of niraparib did well. They still may have required dose reduction to 100 mg, but in general, the dose reduction rate was less, and the nice thing is that they saw equal efficacy in exploratory analysis. For the individualized starting dose, the overall population still had a PFS hazard ratio of 0.68, which is comparable to the 0.62 before individualized dosing.⁶

I’m a simple person, so I like simple dose reductions. Niraparib is 300 mg, 200 mg, 100 mg, so it’s just 100 mg less with every reduction. Olaparib is a little more nuanced, but still important; it’s 300-mg twice daily dosing, then 250 mg twice daily, then 200 mg twice daily. There are more dose reductions with olaparib and rucaparib.

The phase 3 PRIME study data for individualized niraparib dosing was presented. They looked at the weights and plates dosing in a prospective fashion. The study was done in China, and the results are reemphasizing the role of PARP inhibitors in this population with advanced ovarian cancer. These were all-comers. With the individualized starting dose, we saw comparable results, so you can see the PFS hazard ratio was 0.45 in the [intention-to-treat population], with a clear benefit in the HRD, germline BRCA mutation, and nongermline BRCA mutation patient populations.

This highlighted the role of PARP inhibitors in this first-line setting [and] advocated for the role of the weights and platelets, so you can use [these] data to reassure your patients that you’re not compromising their outcomes by starting them at that lower dose. They still need that same monitoring, they still may have dose reductions, but you can see that the AEs leading to discontinuation was low. There were still dose reductions at 40%, but lower than what we initially saw. A dose discontinuation rate of 6.7% was great to see.⁷

_REFERENCES

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_{2. Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1721-1731. Published correction appears in Lancet Oncol. 2021;22(12):e539.}

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_{4. Monk BJ, Han S, Pothuri B, et al. Efficacy of niraparib therapy in patients with newly diagnosed advanced ovarian cancer by BRCA and homologous recombination status: PRIMA/ENGOT-OV26/GOG-3012 study. Presented at: Society of Gynecologic Oncology 2020 Annual Meeting on Women’s Cancer.https://bit.ly/3Mv8ZWK}

_{5. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361}

_{6. Zejula. Prescribing Information. GlaxoSmithKline; 2020. Accessed October 14, 2022. https://bit.ly/3TiRyei}

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