Willmott Reviews Updates From PARP Inhibitor Maintenance Trials for Ovarian Cancer

Lyndsay Willmott, MD

Chief of Gynecologic Oncology

Banner University Medical Center

Gynecologic Oncologist

Arizona Center for Cancer Care

Phoenix, AZ

CASE SUMMARY

• A 49-year-old woman with abdominal bloating and nausea was referred
  to a gynecologic oncologist by her primary care physician.
• Medical history: mild hypertension
• Family history: Mother died of breast cancer at age 59 years; cousin on mother’s side died of ovarian cancer at age 65 years.
• CT scan: small-volume ascites, bilateral 8-cm adnexal masses
• Cancer antigen (CA) 125 level: 285 U/mL
• She underwent exploratory laparotomy followed by omentectomy, bilateral salpingo-oophorectomy, and resection of peritoneal nodules for stage IIIC high-grade serous carcinoma.
  • Optimal cytoreduction with < 1 cm of residual disease after surgery
• Germline molecular testing: BRCA wild type
• Myriad myChoice CDx: homologous recombination deficiency (HRD): ≥ 42
• She was treated with intravenous carboplatin and paclitaxel with NK1, 5HT3, and prophylaxis for dexamethasone chemotherapy–induced nausea and vomiting.
  • She experienced persistent daily nausea with vomiting on day 1 after chemotherapy.
• After completion of chemotherapy, her CA 125 level was 14.2; clinically,
  there was no evidence of disease.
  • Patient reports continuing daily nausea.

Targeted Oncology: Which trial data support olaparib maintenance therapy after first-line chemotherapy?

WILLMOTT: The phase 3 SOLO-1 trial [NCT01844986] was specifically in patients with BRCA mutations, which could have been somatic, though most patients had germline mutations. They had at least a partial response [PR] to their platinum-based chemotherapy.

They were randomly assigned to receive olaparib [Lynparza] vs placebo in a 2:1 ratio. The primary end point was investigator-assessed progression-free survival [PFS], and secondary end points included [time from randomization to second progression], overall survival [OS], time to first subsequent therapy or death, time to second subsequent therapy or death, and health-related quality of life.

As [is typical] for patients with a BRCA mutation, the patients in this clinical trial were slightly younger. Most patients had a complete response [CR] to their chemotherapy, but some patients only had a PR, and these are higher-risk patients in the standard nomenclature for risk stratification. Most patients had serous histology, which also is the most common histology we see in patients with ovarian cancer.¹

The most [recent] updated 7-year survival data were reported in 2022. The median OS was not reached in the olaparib arm vs 75.2 months in the placebo arm [HR, 0.55; 95% CI, 0.40-0.76; P = .0004].² When we first started using PARP inhibitors, there was a question about whether PARP inhibitor maintenance would change the biology of these tumors and perhaps make them a little bit more aggressive. But there has been no detriment to OS or time to subsequent therapies in patients who received olaparib.

All subgroups benefited from olaparib maintenance. Obviously, we want to evaluate whether patients had some worsening issues in terms of toxicity over time, and there were none. There was no significant difference in patients with a diagnosis of MDS [myelodysplastic syndrome] or AML [acute myeloid leukemia], which is very important because these are risks of extreme importance. There was not really a difference in terms of new primary malignancies. Obviously, patients [receiving] olaparib had a slightly higher risk of pneumonitis, a rare but known toxicity of that medication.^1,2

We are aware of the adverse events [AEs] of PARP inhibition. [These are] the big 3 toxicities, which include gastrointestinal [GI] AEs, especially nausea; cytopenia, including anemia or neutropenia; and fatigue. These are exactly what we would expect to see. No new toxicity signals were seen as more follow-up [data were] accumulated and only 1 case of MDS has been reported since the initial data cutoff.²

Q:What is different about the study of bevacizumab plus olaparib?

The most unique thing about the phase 3 PAOLA-1 trial [NCT02477644] was that it’s comparing [olaparib] not just with a placebo like in SOLO-1, but it is comparing it with a known, active drug, bevacizumab [Avastin]. This was a European investigator-sponsored trial, which I think is impressive. Patients who had received platinum-based doublet chemotherapy plus bevacizumab and had at least a PR were eligible.

This, unlike SOLO-1, was available to all comers. Patients did not have to have a BRCA mutation to enroll, but there was a retrospective assessment of patients looking at their HRD status. The patients were randomly assigned to receive maintenance olaparib at the traditional starting dose of 300 mg twice daily for 2 years, just like in SOLO-1, plus bevacizumab, which continued for 15 months vs placebo plus bevacizumab. The primary end point for this trial was investigator-assessed PFS.³

A unique secondary analysis was done for PAOLA-1 looking at the concept of higher- and lower-risk subgroups. I don’t think we can call any patients with advanced ovarian cancer low risk, but there are some higher-risk features. Patients who had stage IV disease, patients who had surgery but had residual disease, and patients who required neoadjuvant chemotherapy are our historical high-risk patients.

Patients who underwent an upfront cytoreduction with no gross residual disease would be our lower-risk subgroup. Generally, I think it’s important to recognize that PAOLA-1 was not a cherry-picked population. There were a lot of high-risk patients like those who had neoadjuvant chemotherapy, with residual disease at the time of their interval cytoreduction, and patients who had only a PR to their chemotherapy. We’re not just looking at patients who responded to their chemotherapy without disease events.³

Updated OS [data were] presented at ESMO [European Society for Medical Oncology Congress] in 2022 and were broken down based on the subgroup. Remember, the intention-to-treat population were all-comers. The subgroup analyses were based on BRCA positivity and HRD status. As we’ve seen in all our PARP inhibitor trials, patients with BRCA mutations seem to respond best to the addition of olaparib, but HRD-positive patients also had impressive separation of the curves compared with patients who received placebo plus bevacizumab.⁴

The FDA indication based on this clinical trial stated that patients with HRD-positive status who had received bevacizumab as a component of their upfront therapy should be considered for bevacizumab plus olaparib. Unfortunately, the patients with homologous recombination–proficient [HRP] status did not have any benefit with the addition of olaparib, so those patients did not receive the indication.⁵

[Many of us] would consider carboplatin and paclitaxel for our patient who had surgery. A lot of us think if the patient had surgery and all the disease was resected, why would we want to add bevacizumab? But the lower-risk group had a profound separation of the curves in patients who received olaparib plus bevacizumab vs bevacizumab alone.

A lot of us perhaps wouldn’t have even considered giving them the bevacizumab, but I think it just gives us an opportunity to pause and think why we are not considering bevacizumab, even in patients who had an excellent surgical cytoreduction, especially if they’re good candidates for bevacizumab. I think it’s not something that we should just take off the table.

The 5-year OS secondary analyses [by risk group] have some error built into them, but are very interesting in terms of hypothesis generation [Table⁶]. They allow us to perhaps reconsider why some say that some patients shouldn’t be considered for bevacizumab or bevacizumab plus olaparib in maintenance. The HRP group unfortunately had no significant improvement with olaparib. We can recognize that there is a slight differential in terms of how well patients do based on their tumor testing and based on this clinical trial.

The toxicities were very similar to [those in] the SOLO-1 trial in terms of PARP inhibitor toxicities, but when we add in the bevacizumab, we see there is a higher risk of hypertension. Hypertension is a known risk of bevacizumab and certainly we saw that in this clinical trial.³

Q:Please discuss niraparib maintenance therapy use in high-risk first-line ovarian cancer.

The phase 3 PRIMA trial [NCT02655016] used niraparib [Zejula]. The clinical trial aimed to evaluate patients who had high-risk ovarian cancer. To enroll, candidates had to have high-risk features; either they had been on neoadjuvant chemotherapy or had residual disease after surgery. Every patient could enroll. They didn’t have to have a BRCA mutation.

They were [randomly assigned] in a 2:1 fashion to niraparib vs placebo. A slight difference from the olaparib trials, which continued for 2 years in maintenance, this trial continued niraparib for 3 years. The primary end point was PFS by blinded independent central-radiology review, and the secondary end point was OS.⁶

The baseline demographics were very similar. Obviously, because this was a high-risk group, we would expect to see some higher-risk features, including 66% of patients having received neoadjuvant chemotherapy. In this trial, one of the things they were assessing was the idea of an individualized starting dose of niraparib.

The traditional starting dose was 300 mg daily, but they assessed an individualized starting dose based on weight. Patients with a weight of less than 77 kg or platelet count less than 150,000 cells/µL were on a 200-mg starting dose. The goal, of course, was to see if we could mitigate some of the toxicity associated with the 300-mg starting dose.⁷ The PFS looked at the overall population and then the BRCA-mutational and HRD status.

Patients with BRCA mutations had the most profound improvement in PFS with niraparib vs placebo. Patients who had HRD-positive status, not attributable to a BRCA mutation, also had quite a significant separation of their curves. The HRP group had a separation of curves, perhaps less dramatic, and a statistically significant improvement in PFS. Based on this assessment and the subgroup break-downs, the FDA indication for niraparib is in all-comers.⁸ All patients, regardless of HRD status, are candidates for niraparib after they’ve completed their chemotherapy, if they’ve had at least a PR.

The safety data for niraparib are very similar in terms of the big 3 toxicities [GI toxicity, cytopenia, fatigue]. One of the big differences is that in the olaparib trials we saw some anemia and not an insignificant amount of grade 3 anemia. In this trial, we saw cytopenia, especially thrombocytopenia and anemia. Even with the individualized starting dose, there’s still a significant number of patients who required some sort of intervention related to cytopenia.

Perhaps it was a little bit better than starting everyone at 300 mg. It’s very important to be aware that there is still significant risk of cytopenia with niraparib. One significant difference between the drugs is that for olaparib, when you start it, the recommendation is to do complete blood counts [CBCs] monthly. For niraparib, the recommendation is to do CBCs weekly until 1 month. We see a lot of the toxicities very early. At 1 month, it’s OK to then go to monthly testing.

A prespecified interim analysis of OS was done. The OS event rates at this point are low, and conclusions can’t be drawn from these data. [OS data] will be presented at a future meeting once the data are a little bit more mature.

_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. DiSilvestro P, Banerjee S, Colombo N, et al; SOLO1 Investigators. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J Clin Oncol. 2023;41(3):609-617. doi:10.1200/JCO.22.01549}

_{3. 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}

_{4. Ray-Coquard I, Leary A, Pignata S, et al. Final overall survival (OS) results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib (ola) plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC). Ann Oncol. 2022;33(suppl 7):S1396-1397. doi:10.1016/j.annonc.2022.08.025}

_{5. FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. FDA. Updated May 11, 2020. Accessed May 29, 2023. https://bit.ly/43Lg65a}

_{6. Lorusso D, Mouret-Reynier MA, Harter P, et al. 5-year (y) overall survival (OS) with maintenance olaparib (ola) plus bevacizumab (bev) by clinical risk in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) in the phase III PAOLA-1/ENGOT-ov25 trial. ESMO Open. 2023;8(suppl 1):100812. doi:10.1016/j.esmoop.2023.100812}

_{7. 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}

_{8. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. FDA. April 29, 2020. Accessed June 16, 2023. https://bit.ly/3UYgh9f}