Treatment Complexities Continue to Mount in Gynecologic Cancers

Michael J. Birrer, MD, PhD

Data concerning the long-term benefit of PARP inhibitors as maintenance therapy for select patients with ovarian cancer in later-line settings have come under fire in 2022 as several agents have failed to demonstrate improvements in overall survival (OS) outcomes.^1-3 These data readouts have resulted in recommendations from the FDA, the Oncology Drug Advisory Committee (ODAC), and the drug sponsors for the removal of indications for rucaparib (Rubraca), niraparib (Zejula), and olaparib (Lynparza) in heavily pretreated patients with BRCA-mutant ovarian cancer.^1-3

The removal of indications is only one of the stories being told in ovarian cancer this past year. In a recent OncLive Peer Exchange®, an expert panel of gynecologic oncologists highlighted areas of ongoing research that have demonstrated improvements for frontline maintenance therapies as well as advances in the novel agents for patients with recurrent disease.

“It was easier when it was just carboplatin and paclitaxel, now we have a lot of choices with these active drugs,” Michael J. Birrer, MD, PhD, said. “Stratifying patients more carefully with biomarkers is going to be important, [as well as] working work with our regulatory [partners] to get a consensus on OS vs [progression-free survival] PFS because the field of ovarian cancer is now moving toward [where] non–small cell lung cancer is [in terms of using outcomes], and we need to have the same sort of agreement on how we’re going to go forward [with data to support indications]. One of the ways we could effectively do that is to point out that we can stratify our patients better, for example with homologous recombination deficiency [HRD] testing.”

The voluntary withdrawal of indications for heavily pretreated patients with BRCA-mutated ovarian cancer stem from OS data reflecting HRs that failed to demonstrate a benefit with prolonged PARP inhibitor therapy in this patient population.^1-4 The manufacturers of niraparib, olaparib, and rucaparib each issued statements that the data no longer support the use of these agents. “[What happens with] these dear doctor letters is the sponsor says we looked at the data, we had conversations with the FDA, we decided to withdraw this accelerated approval for whatever reason, right or wrong,” Bradley J. Monk, MD, said.

Bradley J. Monk, MD

The voluntary withdrawal of indications began in June 2022, when Clovis removed the indication for rucaparib for patients with BRCA-mutated ovarian cancer after at least 2 prior chemotherapies in the United States and Europe. The FDA granted accelerated approval to the PARP inhibitor in December 2016 for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer following 2 or more chemotherapies. In 2 open-label, single-arm trials, investigator- assessed ORR was 54% with a median duration of response of 9.2 months.⁵

In November 2022, the FDA issued a notice to Clovis requesting that the company limit the use of rucaparib to second-line maintenance therapy for patients with recurrent ovarian cancer harboring BRCA mutations. If the 2 sides cannot reach an agreement on the revised indication, the FDA said it would convene an ODAC meeting to review the matter.

In August 2022, AstraZeneca and Merck notified providers that olaparib was no longer indicated for adults with BRCA-mutated advanced ovarian cancer who have received at least 3 prior lines of chemotherapy following a safety analysis of the phase 3 SOLO3 trial (NCT02282020). At a median follow-up of 48.9 months in patients who received 2 or more lines of prior chemotherapy, olaparib monotherapy elicited a median OS of 34.9 months. At a median follow-up of 25.4 months, patients who were administered chemotherapy experienced a median OS of 32.9 months (HR, 1.07; 95% CI, 0.76-1.49).

In an evaluation of patients who received at least 2 lines of therapy, 65.2% of those who received olaparib died by the April 2021 data cutoff compared with 52.3% of those assigned to chemotherapy. For patients who received 3 or more prior lines of chemotherapy, 70.0% of patients in the olaparib arm had died compared with 54.8% of those assigned to chemotherapy.⁴

Finally, niraparib was indicated for use with patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with 3 or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)–positive status.6 In September 2022, GSK notified providers that investigators identified “a potential detrimental effect” on OS in patients treated with other PARP inhibitors in trials evaluating niraparib as third-line or later therapy for patients with BRCAmutated advanced ovarian cancer.

The review of the indication was scheduled to undergo review by ODAC considering the release of survival data from the phase 3 NOVA study (NCT01847274); however, the meeting was cancelled in October 2022 after the agency cited that the meeting was no longer needed.⁷ In September 2022, the indication for the treatment of patients with HRD-positive ovarian cancer after 3 or more prior lines of chemotherapy was removed.3 The data from the NOVA study will be presented during a plenary session from the European Society for Medical Oncology (ESMO).⁸ In November 2022, the manufacturer restricted use of the agent as a secondline maintenance strategy to only patients with deleterious or suspected deleterious germline BRCA mutations. The frontline maintenance indication remained unchanged.⁵

“This [decision] harks back to the infectious nature of this dear doctor stuff,” Birrer said. “In this case, to a certain extent, the sponsor is seeing a very shrinking market for these agents because the median [lines of prior therapy in the studies] is 4 lines or more, every [patient] is getting PARP [inhibition] upfront and that’s good. [Related] to that is the concern about these preliminary OS interpretations with HRs and CIs extended over 1. The general [precedent] is not a good one [and] some work needs to be done to educate both the community oncologists and then also we need discussions with the FDA.”

What appeared to be an emerging trend for these agents in this population was a concern for Monk. “We’re advocates for patients,” Monk said. “In our everyday practice we have seen patients who for whatever reason haven’t seen a PARP inhibitor [as a] later line of therapy, where chemotherapy in my experience is not very effective…. These randomized trials put that [choice] into question—[outcomes showed] the PARP inhibitors improves response rates, they improved progression-free survival [PFS]. The influence on OS is maybe in settings that are not relevant to my practice pattern.”

Progress in the Front Line

“The science has been around since 2018 and we also have data from 2012 saying that there is a strong relationship between BRCA mutation and the expectation for treatment to PARP,” Robert L. Coleman, MD, FACOG, FACS, said, adding that there is confidence using PARP maintenance in the frontline setting.

Robert L. Coleman, MD, FACOG, FACS

“The unified [opinion] is that every patient with a BRCA mutation and newly diagnosed advanced ovarian cancer that responds to platinum needs a PARP inhibitor,” Monk said. “I’m less passionate about which PARP inhibitor.”

Olaparib

Two years of olaparib maintenance therapy elicited a long-term OS benefit vs placebo in patients with newly diagnosed, advanced ovarian cancer harboring a BRCA mutation, according to 7-year follow-up f indings from the phase 3 SOLO1/GOG-3004 trial (NCT01844986) presented at the 2022 ESMO Congress and simultaneously published in the Journal of Clinical Oncology.^9,10

“We are really familiar with SOLO1, in which patients are treated up front: They had their primary platinum treatment and a benefit of some kind and were randomly assigned between olaparib for 2 years or placebo,” Shannon N. Westin, MD, MPH, FACOG, said. “We’ve seen presentations of the PFS data which have remained very solid at an HR of 0.33 so these patients are living longer without progression.”

Shannon N. Westin, MD, MPH, FACOG

As of the data cutoff of March 7, 2022, the median OS was not reached with olaparib compared with 75.2 months with placebo (HR, 0.55; 95% CI, 0.40-0.76; P = .0004). The 7-year OS rates were 67.0% in the olaparib arm and 46.5% in the placebo arm. The median duration of follow-up in the olaparib and placebo arms was 88.9 months (range, 85.7-93.6) and 87.4 months (range, 84.391.7), respectively.⁹

At data cutoff, 45.3% of patients in the olaparib arm and 20.6% in the placebo arm had still not received a first subsequent treatment, while 44.3% of patients given placebo received a PARP inhibitor in a subsequent line of therapy, compared with 14.6% of patients in the olaparib group.

“What’s always been really exciting about the PFS and now the OS curves is that we anticipated that the patients with BRCA mutations do the best and so we thought maybe the control arm would perform better,” Westin said, adding that these patients are younger and healthier and typically respond better to treatment. “That’s not what we’re seeing. We are seeing consistent benef it in that patient population with the use of the PARP inhibitor.”

No new safety signals were observed during the 7-year follow-up. The incidence of myelodysplastic syndrome/acute myeloid leukemia remained low in the olaparib and placebo arms (1.5% vs 0.8%, respectively) and new primary malignancies remained balanced between arms (5.4% vs 6.2%). Pneumonitis occurred in 5 patients treated with olaparib.⁹

A combination of bevacizumab (Avastin) and olaparib was evaluated as a frontline treatment for patients with ovarian cancer who had a response to chemotherapy and no evidence of disease remaining in the phase 3 PAOLA-1/ ENGOT-ov25 trial (NCT02477644). At the ESMO Congress 2022, data from the final OS analysis showed a clinically meaningful improvement after a median follow-up of 61.7 months (range, 57.5-67.0) in the olaparib arm and 61.9 months (range, 58.1-66.8) in the placebo arm. The median OS in the intention-to-treat (ITT) population was 56.5 months vs 51.6 months, respectively (HR, 0.92; 95% CI, 0.76-1.12; P = .4118). Moreover, OS rates at 5 years were 47.3% with the addition of olaparib compared with 41.5% with placebo.¹¹

In patients with tumors positive for HRD, the addition of olaparib to bevacizumab maintenance therapy reduced the risk for death by 38% (HR, 0.62; 95% CI, 0.45-0.85), with 5-year OS rates of 65.5% with the combination regimen and 48.4% with placebo. This benefit was consistent across patients who harbored a BRCA mutation (5-year OS rates, 73.2% vs 53.8%, respectively; HR, 0.60; 95% CI, 0.39-0.93) and those who did not (5-year OS rates, 54.7% vs 44.2%; HR, 0.71; 95% CI, 0.45-1.13). However, no benefit was seen in HRD-negative patients (5-year OS rates, 32.3% vs 25.7%, respectively; HR, 1.19; 95% CI, 0.88-1.63).¹¹

“It’s difficult to really call [bevacizumab alone a] control arm,” Birrer noted in a discussion of the trial design. “In some regard that explains the results, which are that there was a statistically significant OS prolongation in the HRD population, which included BRCA or no BRCA mutation. If you look at the ITT [data], it has an HR of 0.92, which is not statistically significant. In the HRD population it certainly was, with an HR of 0.62. Very impressive.”

Westin noted that even though more clinicians are using bevacizumab now, “it took a long time to get there. We’re seeing more bevacizumab use in the community.” Considering that, data from longer follow-up are emerging to that may influence treatment schemas for maintenance therapy. A recent study published in the Journal of Clinical Oncology signaled that bevacizumab beyond 15 months did not improve PFS in patients with newly diagnosed stage IIB to IV ovarian cancer.¹²

Data from the phase 3 BOOST trial (NCT01462890) showed that among 2 cohorts of patients with ovarian cancer receiving bevacizumab, there was no difference in PFS between the treatment arms (HR, 0.99; 95% CI, 0.851.15; P = .90). The median PFS with 15 months of treatment was 24.2 (95% CI, 22.2-26.5), and extended treatment of 30 months yielded a median PFS of 26.0 months (95% CI, 23.7-29.7). OS outcomes were also similar between the 2 arms (HR, 1.04; 95% CI, 0.87-1.23; P = .68).¹²

Niraparib

Monk noted that the update from the phase 3 PRIMA trial (ENGOT-OV26/GOG-3012; NCT02655016) is the pivotal trial supporting the argument for HRD testing. In the latest results, maintenance treatment with niraparib produced a sustained and durable PFS benefit in patients with primary advanced ovarian cancer who responded to first-line platinum-based chemotherapy, spanning biomarker subgroups.¹³

At a median follow-up of 3.5 years, the median PFS with niraparib was 24.5 months per investigator assessment vs 11.2 months with placebo in the HRD population (n = 373; HR, 0.52; 95% CI, 0.40-0.68; P < .001). In the overall population (n = 733), the median investigator-assessed PFS with niraparib was 13.8 months vs 8.2 months with placebo (HR, 0.66; 95% CI, 0.56-0.79; P < .001).¹³ Treatment with niraparib boosted the duration of PFS vs placebo across the biomarker subgroups examined. The greatest benefit was observed in those with HRD tumors that were BRCA mutated (HR, 0.45; 95% CI, 0.32-0.64).

“It was nice to see that the curves [with longer-follow up] are parallel. They continued to parallel out with over 3 years. It’s confirmation across analytical end points providing more confidence that [niraparib] works in those with biomarker-positive mutations,” Coleman said.

Rucaparib

Rucaparib maintenance therapy improved PFS vs placebo in patients with newly diagnosed ovarian cancer, according to disease risk subgroup analyses from the phase 3 ATHENA–MONO study (NCT03522246).¹⁴ Among patients with HRD, the median PFS was 28.7 months with rucaparib vs 11.3 months with placebo (HR, 0.47; 95% CI, 0.31-0.72; log-rank P = .0004). In the overall population, the median PFS was 20.2 months vs 9.2 months, respectively (HR, 0.52; 95% CI, 0.40-0.68; log-rank P < .0001). Notably, the 24-month PFS rate in the ITT population was 45.1% vs 25.4% for rucaparib and placebo, respectively. The benefit of rucaparib was consistent across subgroups.¹⁴

PFS was also assessed in terms of response to first-line chemotherapy. Among patients who achieved a partial response, the median PFS was 14.8 months (95% CI, 9.1-25.6) and 9.1 months (95% CI, 3.5-9.2; HR, 0.43; 95% CI, 0.18-1.02) in the HRD population and 12.2 months (95% CI, 9.2-19.7) and 6.4 months (95% CI, 3.7-9.2) in the ITT population following treatment with rucaparib and placebo, respectively. Among complete responders (CRs), the median PFS was 25.8 months (95% CI, 17.4-not reached [NR]) and NR (95% CI, 2.5-NR) in the HRD population following treatment with rucaparib and placebo, respectively. In the ITT population, the median PFS was 15.6 months (95% CI, 10.2-25.8) and 6.4 months (95% CI, 2.7-NR; HR, 0.48; 95% CI, 0.231.03), respectively. Safety was similar across patient subgroups.

“We have these 3 PARP inhibitors, olaparib, niraparib and rucaparib, [with the rucaparib data showing benefit] in the BRCA, HRD, and the HRD-negative subsets,” Monk said noting that rucaparib is not yet approved, but that applications to the FDA and European Medicines Agency are submitted.¹⁵

Birrer, Westin, and Monk all agreed that testing becomes important for these patients. Monk noted, “You have to do 2 things to [take advantage of the PAOLA-1 opportunity: You [must give patients] bevacizumab and you must have molecular testing of the tumor [for HRD].” Coleman added, “As we get better with respect to [identifying and using] these biomarkers to guide treatment, patients are going to benefit and we’ll [know better which] patients shouldn’t [receive PARP maintenance]. I’m OK with the science continuing to move in that direction.”