Part 1: PARP Inhibition Recommendations in Advanced Ovarian Cancer

Matthew L. Anderson, MD, PhD
Director, College of Medicine Obstetrics & Gynecology
USF Morsani College of Medicine
Associate Director for Shared Resources
Cancer Institute at Tampa General Hospital
Tampa, FL

Targeted Oncology^TM: Have the PARP inhibitors from the SOLO-1 (NCT01844986), PRIMA (NCT02655016), and PAOLA-1 (NCT02477644) studies been incorporated into the NCCN (National Comprehensive Cancer Network) guidelines?

ANDERSON: Based on these data, in a remarkably rapid fashion, the NCCN guidelines have been updated to reflect options for use of these combinations.¹ In the guidelines, if you have a patient with stage II, III, or IV ovarian cancer, the standard of care remains some type of platinum-based chemotherapy regimen and best supportive care to control symptoms. As part of that, you need [to] incorporate surgical debulking, which is not included as part of these guidelines. But once you have concluded that primary therapy of 6 cycles of carboplatin and paclitaxel [Taxol] and the patient has obtained either a complete response [CR] or partial response [PR], they now become eligible for maintenance therapy.

What are the NCCN recommended guidelines for PARP inhibitors used in maintenance therapy?

How the NCCN provides options to utilize these medications in part depends on whether you as [the patient’s] primary oncologist have elected to incorporate bevacizumab [Avastin] into the treatment plan.¹ This is not the case for all practices and what we do here at Tampa General [Hospital is] use this routinely for our patients, but that’s not everybody’s practice. In addition, when you go over all the adverse events [AEs] of bevacizumab, patients hear certain types of AEs [and] they’re not interested in this medication. Regardless of your choice or the patient’s choice, there are options for maintenance therapy among these 3 trials that allow us to address the needs or concerns of patients regardless of whether they’ve used bevacizumab.^2-4

For patients who have not used or received bevacizumab during their primary therapy—if these patients are BRCA1/2 wild type or their homologous recombination or BRCA status is unknown and they’ve had a CR or PR—you have 2 options.¹ The NCCN guidelines would suggest observation, which has been the standard of care now for many years, or you offer those patients niraparib [Zejula], which is a legitimate option with the goal of reducing disease recurrences. That does result in a significant improvement in the PFS [progression-free survival] of these patients that, in terms of magnitude, is like the use of bevacizumab by itself.

If the patient, however, has not received bevacizumab but is germline or somatic BRCA mutated and has either stable disease or progression, then they would not be eligible for the use of a PARP inhibitor.¹ Under those circumstances, the likelihood that a PARP inhibitor would produce clinical benefit is quite low. The best predictor for these patients about whether that tumor is going to respond to a PARP inhibitor is whether their initial tumor responded to platinum therapy and remains platinum sensitive.

How does your recommendation differ for patients who have received bevacizumab?

If the patient has received bevacizumab as part of their primary therapy, at the time they conclude carboplatin and paclitaxel chemotherapy plus the bevacizumab, you then have some options based on what their genomic profiling looks like. For patients who [have tumors that are] BRCA1 or BRCA2 mutated, either germline or somatic mutations or unknown, who had a CR or PR but who are homologous recombination proficient, then the option is bevacizumab alone.¹

The only study that looked at the combination has relied on olaparib [Lynparza]. No mutations in other genes involved in homologous recombination that we know predispose patients to developing ovarian cancer. Those patients, if they’re proficient in all those genes [and] there are no new high-risk mutations, then they’re not eligible for the use of olaparib and you would want to continue with the use of bevacizumab for that remaining 12 months for which they’re eligible.¹

However, if they are homologous recombination deficient [HRD], high-risk mutation, BRCA1 or BRCA2, then they’re eligible for the combination of bevacizumab plus olaparib, which offers some very impressive improvements in PFS for these patients.^1,4 If the patient is known to have a BRCA1 and BRCA2 mutation, that’s the best combination of all, because not all patients are going to have BRCA1 and BRCA2 mutation and/or a mutation of one of these other genes. You will see subsets of patients who have a mutation of one of these other gene products involved in homologous recombination but have a wild type BRCA1 or BRCA2 mutation. If they’re BRCA1 or BRCA2 wild type but they have a mutation of one of these other homologous recombination genes and then got bevacizumab, they are eligible for the combination of olaparib plus bevacizumab.¹

Best of all, if they have a combination of germline or somatic BRCA1 mutations and they have a CR or PR, now they’re eligible for bevacizumab, also olaparib—or olaparib or niraparib.¹ Regardless of whether they’ve gotten that carboplatin plus paclitaxel plus bevacizumab at the conclusion of their primary therapy, [if] they have disease progression, or it hasn’t responded at all, then those patients are not going to be a candidate for a PARP inhibitor.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 3.2021. Accessed December 13, 2021. https://bit.ly/3qhWapj}

_{2. 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}

_{3. González-Martín 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}

_{4. 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}