Anderson Explains Benefits of PARP Inhibitors in Ovarian Cancer

Matthew L. Anderson, MD, PhD

The case of a 49-year-old African American woman with ovarian cancer was discussed during a virtual Case Based Peer Perspective event led by Matthew L. Anderson, MD, PhD, director, College of Medicine Obstetrics & Gynecology, associate professor, University of South Florida Morsani College of Medicine, medical director, Office of Clinical Research, Tampa General Hospital in Tampa, FL.

Targeted Oncology™: What’s the rationale for using a PARP inhibitor in patients with ovarian cancer?

ANDERSON: In the past 5 years, we have witnessed the introduction of PARP inhibitors based on 3 seminal trials that examined and demonstrated how the use of these agents can be integrated into clinical practice.

The biology behind this is quite impressive. If a patient’s tumor has a defect—it could be an inactivation, a point mutation, or chromosomal rearrangements in BRCA1/2—that is involved in the repair of double-stranded DNA damage by homologous recombination, that defect creates what’s called a synthetic lethal phenotype that sensitizes tumors to the use of a PARP inhibitor.

If the DNA is damaged resulting in single-strand DNA damage, the cell attempts to repair this by converting the single-strand DNA damage using mechanisms powered by the PARP enzyme. If the PARP enzyme is inhibited so that the cell can no longer be repaired, it leads to a mitotic crisis and cancer cells die.

One of the primary ways in which carboplatin works is to induce single-stranded DNA. In the presence of a PARP inhibitor, the cells can no longer fix that damage. The cells that are defective in homologous recombination now lack a way to survive the lethal one–two hit of these 2 drugs, and as a result, it’s a highly effective way to sensitize cancer cells to treatment.

This method is remarkably effective, and essentially it’s a phenotype that has no effect on cells that are wild type or have homologous recombination. [As a result], it should not have a lot of lethality or cause problems in other normal populations of cells.

What were the seminal trials that helped determine how PARP inhibitors can be integrated into the first-line treatment of ovarian cancer?

These trials were SOLO-1 [NCT01844986], PRIMA [NCT02655016], and PAOLA-1 [NCT02477644].^1-3

SOLO-1 evaluated olaparib [Lynparza] maintenance therapy after the completion of standard-of-care first-line chemotherapy. The study enrolled a subset of patients with ovarian cancer who by definition were required to have inactivating BRCA1/2 mutations. All the patients had newly diagnosed high-risk ovarian cancer. They had stage III or IV [disease]. They could not have been previously treated with other types of targeted agents, but most importantly, they all had to have completed that standard-of-care platinum-based chemotherapy.

If you look at the types of mutations that were found in the patient population enrolled in this study, the overwhelming majority had some type of a germline BRCA1/2 inactivating mutation or genomic rearrangement.

The investigators reported an improvement in the 3-year progression-free survival [PFS], increasing from 27% in patients who received only carboplatin and paclitaxel to 60% in patients who remained on bevacizumab [Avastin] or were placed on olaparib following carboplatin and paclitaxel [HR, 0.30; 95% CI, 0.23-0.41; P < .001].

How did the results from PRIMA build on the findings from SOLO-1?

The PRIMA study…examined the use of niraparib [Zejula] versus placebo in patients with high-risk ovarian cancer with any BRCA status. In addition, another important inclusion in this study population was patients who did not have high grade serous carcinomas. Rather they had high-grade endometrial cancers, and as part of this analysis, homologous recombination deficiencies were assessed using the Myriad myChoice HRD test.

Interestingly, there are other types of defects that can occur in homologous recombination that involve gene products other than BRCA1/2. In addition, there can be other genes that are important for determining or creating a defect in homologous recombination. This phenotype is not well understood, and most importantly, it is not completely defined by patterns of gene mutations that we might observe or that might be reported on the types of clinical testing platforms that we use to genetically profile patients with ovarian cancer.

PRIMA compared the efficacy of niraparib to placebo in a population of frontline patients with ovarian cancer but expanded the study eligibility to include BRCA wild–type tumors.

If we look at the outcomes, the investigators reported a significant improvement in PFS from 8.2 to 13.8 months at the 24-month interim analysis [HR, 0.62; 95% CI, 0.50-0.76; P < .001].

Looking at patient subsets, the investigators reported that PFS was best among patients who had an inactivating mutation in BRCA1/2. For the 71 patients who received placebo, there was an improvement in median survival from 10.1 months to 22.1 months that was statistically significant [HR, 0.43; 95% CI, 0.31-0.59; P < .001].

The patients most likely to benefit are those patients who carry some type of inactivating mutation in BRCA1 or BRCA2. The benefit is lowered in patients with homologous recombination deficiency and who do not have a BRCA mutation. Those who benefited least were patients with a homologous recombination proficiency.

Survival improved in the overall study population at 2 years from 77% to 84%. This was particularly impressive for patients who are homologous recombination deficient and those with homologous recombination–proficient tumors.⁴

How did patients benefit in the PAOLA-1 trial?

Patients who received the combination of bevacizumab and olaparib had a longer disease-free interval compared with patients treated with bevacizumab alone. PFS was measured at 3 points: at 12 months, 18 months, and 24 months. At 12 months, PFS was 78% for the combination versus 66% for the control; at 18 months, 62% versus 46%, [respectively]; and at 24 months, 46% versus 28%.

Similar to the previous studies, the patients who carried BRCA mutations and had some type of deficiency in homologous recombination were most likely to benefit with improved PFS with the combination of olaparib and bevacizumab.

What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for this patient?

For patients who have not received bevacizumab [Avastin] during primary therapy, if their mutation status is BRCA1/2 wild type or unknown with a complete remission [CR] or a partial remission [PR], the guidelines recommend observation for CR or niraparib [Zejula].⁵

If the patient has a germline or somatic BRCA1/2 mutation and they have a CR or PR, then you could use olaparib [Lynparza],niraparib, or observation.

Interestingly, homologous recombination deficiencies are not explicitly mentioned in the NCCN guidelines for a patient with this particular disease setting, but I personally would think it’s legitimate to use olaparib.

Are you familiar with the recommended niraparib dose adjustments based on baseline body weight and platelet count?

Most [clinicians] are familiar with the dose adjustment. Niraparib is available in 100-mg capsules, and it should be used at 3 dose levels. It was initially recommended that all patients receive a 300-mg dose per day. That was 3 capsules a day. If dose reduction is needed, it should be reduced to 200 mg, and for a second dose reduction, it should be reduced to 100 mg.

When investigators went back and evaluated the results from the NOVA trial [NCT01847274], they found that patients who had a baseline body weight of 77 kg or a baseline platelet count of less than 150,000…were most likely to experience grade 3 thrombocytopenia and were more likely to have their dose reduced to 200 mg or 100 mg when they were started on the 300-mg dose per day.

On the basis of this observation, it is now recommended that for this subset of patients, an option would be to initially start them at the 200-mg daily dose of niraparib.

Why do patients experience thrombocytopenia more often when taking niraparib rather than olaparib?

This relates to the relative specificities of the 2 different agents for individual PARP inhibitors. There is a strong presence of PARP expressed in platelets. Niraparib shows a particular affinity for the isotype or isoform of PARP that is specifically expressed in platelets.

You may ask how we find ourselves in this strange situation. It probably relates to the statistical outcomes of a phase 1 trial that was used to initially assign the maximally tolerated dose for this drug. That first phase 1 study probably overshot a little bit, so unfortunately the manufacturer of niraparib, Tesaro, would have benefited from having additional data helping to support the definition of that maximally tolerated dose, which led to the 300-mg dose being used as part of their initial clinical trials in NOVA.

When patients receive the reduced dose of 200 mg, it doesn’t have as much of an impact on anemia, but it addresses the problem with thrombocytopenia and improves and reduces the frequency of neutropenia and fatigue.⁶

How do dose reductions of this regimen affect the patients?

Importantly, the patients who needed to have a dose reduction did not experience a deleterious outcome. You can safely dose-reduce to 200 mg and have just as good a clinical outcome than if you had kept somebody who is going to tolerate the 300-mg dose. There’s no detriment in this clinical benefit between using the 2 different doses when you select patients on the basis of that algorithm.

_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. Gonz.lez-Mart.n A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962}

_{3. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investi gators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361}

_{4. Han SN, Monk BJ, Gonzalez-Martin A. Time to fi rst subsequent therapy (TFST) and progression-free survival 2 (PFS2) from the phase 3 randomized, double-blind PRIMA/ENGOT-OV26/GOG-3012 study in patients with newly diagnosed ovarian cancer. Presented at: Society of Gynecologic Oncology 20/20 Annual Meeting on Women’s Cancer; March 27-31, 2020. Accessed July 23, 2020. https://bit.ly/39lKesp}

_{5. NCCN. Clinical Practice Guidelines in Oncology. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 1.2020. Accessed July 21, 2020. htt ps://bit.ly/30gdvlD}

_{6. Berek JS, Matulonis UA, Peen U, et al. Safety and dose modification for patients receiving niraparib. Ann Oncol. 2018;29(8):1784-1792. doi:10.1093/annonc/mdy181. Published correction appears in Ann Oncol. 2019;30(5):859. doi:10.1093/annonc/mdy255}