Targeted therapy approaches have expanded rapidly in ovarian cancer over the past 3 years, with the FDA approving 4 new strategies in frontline settings that allow women to remain free of disease progression longer than the previous standard of care.
Targeted therapy approaches have expanded rapidly in ovarian cancer over the past 3 years, with the FDA approving 4 new strategies in frontline settings that allow women to remain free of disease progression longer than the previous standard of care.1
During an OncLive Peer Exchange®, a panel of ovarian experts discussed the clinical trials that led the FDA to broaden approvals for bevacizumab (Avastin), olaparib (Lynparza), niraparib (Zejula), and the combination of olaparib and bevacizumab in first-line and maintenance settings (TIMELINE).2 They also examined the emergence of homologous recombination deficiency (HRD) as a new biomarker to help guide decision-making.
The pace of change in frontline advanced ovarian cancer has been “pretty impressive,” said Bradley J. Monk, MD, who served as moderator for the program. “Before that, it was almost 20 years since the standard had changed away from cyclophosphamide to paclitaxel,” he said. “It’s a very exciting time.”
Based on data from the phase 3 GOG-0218 trial (NCT00262847), the FDA approved bevacizumab in June 2018 for patients with epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer in combination with carboplatin and paclitaxel, followed by single-agent bevacizumab, for stage III or IV disease after initial surgical resection.3
Panelist Michael J. Birrer, MD, PhD, called it “the granddaddy of the trials” because findings from the study, launched in 2005, led to the introduction of the first biologic agent and targeted therapy for ovarian cancer into clinical practice. Bevacizumab first gained FDA approval in combination with chemotherapy in the recurrent, platinum-resistant setting in 2014.4
In GOG-0218, investigators randomly assigned 1873 women with incompletelyresectable, newly diagnosed stage III or IV disease to standard carboplatin plus paclitaxel chemotherapy followed by placebo maintenance, standard chemotherapy plus concurrent bevacizumab followed by placebo maintenance, or standard chemotherapy plus concurrent and maintenance bevacizumab.
After a median follow-up of 17.4 months, the median progression-free survival (PFS) was 10.3 months in the control group, 11.2 months in the bevacizumab-initiation group, and 14.1 months in the bevacizumab-throughout group. Relative to controls, HR for progression or death was 0.908 (95% CI, 0.795-1.040; P = .16) in the bevacizumab-initiation arm and 0.717 (95% CI, 0.625-0.824; P < .001) in the bevacizumab-throughout arm. There were no significant differences in overall survival (OS) between groups.5
A long-term follow-up of the study for a median of 102.9 months confirmed these findings. Compared with the control arm, HR for death was 1.06 (95% CI, 0.94-1.20) in the bevacizumab-initiation arm and 0.96 (95% CI, 0.85-1.09) in the bevacizumab-throughout arm.6
Although that lack of an OS benefit persisted, Birrer said, “a subset analysis looking at some high-risk patients, like stage IV, suggested that they may have benefited the most and had a survival advantage.” The median OS for patients with stage IV disease assigned to bevacizumab-throughout was 42.8 months versus 32.6 months for similar patients in the control arm (HR, 0.75; 95% CI, 0.59-0.95).
The panelists said the European Medicines Agency approved bevacizumab for the treatment of ovarian cancer in 2011. They noted that it took longer for US approval because OS was considered a key end point by the FDA at that time.
“Back then, we were looking to hit the OS mark,” Leslie Randall, MD, said. “In that interim time, that’s when we had talks with the FDA that OS was not the best end point in ovarian cancer and that the earlier the line of therapy, the more difficult it is as an end point.”
Monk further explained that other factors now weigh more heavily into ovarian cancer approval decisions, including a meaningful PFS benefit, good safety/tolerability, and convenience. Bevacizumab fulfills those other concerns, making the anti-VEGF monoclonal antibody a valuable treatment option in this setting.
In December 2018, the FDA approved the PARP inhibitor olaparib as a maintenance treatment for adults with deleterious or suspected BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to first-line platinum-based chemotherapy based on data from the phase 3 SOLO-1 trial (NCT01844986).7 “[The BRCA mutation] could be either germline or somatic, although as we all know, the majority of these patients did have a germline mutation,” said Shannon N. Westin, MD, MPH, noting that only 2 patients in the trial had a somatic mutation.
In SOLO-1, patients were randomly assigned to maintenance therapy with 300 mg twice-daily olaparib (n = 260) or placebo (n = 131).8 Olaparib was associated with a 70% reduction in the risk for progression or death (HR, 0.30; 95% CI, 0.23-0.41; P < .001) at a median follow-up of 41 months. “We were excited about the hazard ratio of 0.7 [in the GOG-0218 trial], but now here we were with a 0.3—a 70% reduction in the risk of progression,” Westin said.
She added that investigators followed patients in the study and observed some remarkable results. “A year after the majority of those patients had stopped treatment, 60% of the patients on the olaparib arm were progression free compared with 26.9% who were progression free at 3 years who were on placebo,” she said.
Westin explained that these data helped demonstrate that targeted maintenance works in ovarian cancer and that patients can safely stop maintenance therapy. That said, it is still unclear whether olaparib treatment will yield an OS benefit.
“That’s the next big question,” she said. “It’s going to take a while to get that answer, but certainly impressive data that led to an FDA approval for this drug.”
Monk asked the panelists what they thought about the risks of myelodysplastic syndrome (MDS), which has been observed in less than 1.5% of patients who received olaparib monotherapy in clinical trials. Many of those MDS events were fatal.9
“Predictively, that 1% range is certainly something to consider, but when you see such a difference in PFS, we can feel quite confident that olaparib is improving the quality of patients’ lives, and they’re likely living longer,” said panelist Matthew Powell, MD. He added that the olaparib data reflect the benefit of biomarker-directed therapy and that they have driven what he would consider the standard of care for these patients.
Five-year follow-up data presented at the European Society for Medical Oncology Virtual Congress 2020 in October showed that the benefit of olaparib continues substantially beyond the end of treatment. The median PFS observed with olaparib maintenance was 56.0 months compared with 13.8 months in the placebo arm (HR, 0.33; 95% CI, 0.25-0.43).10
In April 2020, the FDA approved niraparib as a maintenance therapy for adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to first-line platinum-based chemotherapy based on data from the phase 3 PRIMA trial (NCT02655016). Unlike SOLO-1, all biomarker populations were included in the study and 50.9% of patients had HRD-positive tumors.11
“This was an interesting trial in that it had entered the worst [prognosis] patients—stage III/IV, high-grade serous or endometrioid who had stage III, primary debulked with visible or residual disease, either neoadjuvant or inoperable— really high-risk disease and all stage IV,” Randall said. “I thought this trial would be negative because of the high-risk population, but it was not. It did show a benefit.”
Patients were assigned to maintenance therapy with niraparib (n = 487) or placebo (n = 246). In the overall study population, the PFS was 13.8 months for niraparib and 8.2 months for placebo (HR, 0.62; 95% CI, 0.50-0.76; P < .001). Among the patients with HRD, the median PFS was 21.9 months in the niraparib group versus 10.4 months in the placebo group (HR 0.43; 95% CI, 0.31-0.59; P < .001).12
“If you then looked at the BRCA wildtype HRD, there was a 0.50 HR,” Randall said, noting she was surprised by these data because she did not expect to see this degree of benefit in the higher-risk population.
“If you looked from the first patient enrolled in PRIMA to the FDA approval on April 29, it was 37 months,” Monk added. “We changed the standard of care in ovarian cancer in all comers in 37 months, [whereas] GOG-0218 took more than 10 years from the time that the study started until it got FDA approval. That’s important.”
Monk also pointed out that PRIMA redef ined how ovarian cancer studies are conducted. “What PRIMA did was very collaborative, not only with the GOG [Foundation] beyond the government, but with our European colleagues [as well],” he said. “That’s the new standard moving forward as these are now international trials with the European Network of Gynaecological Oncological Trial Groups and the GOG.”
In May 2020, the FDA expanded the indication for olaparib to include its combination with bevacizumab for first-line maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to first-line platinum-based chemotherapy and with HRD-positive status defined by either a deleterious or suspected deleterious BRCA mutation and/or genomic instability. Approval was based on the phase 3 PAOLA-1 trial (NCT02477644), in which patients were randomly assigned 2:1 to receive bevacizumab in combination with olaparib at 300 mg twice daily (n = 537) or with placebo (n = 269). Patients continued olaparib for up to 2 years or until disease progression or unacceptable toxicity.13
“It had impressive results,” Powell said of the trial. “It was an amazing difference that we’re seeing, and we’re quite excited.” After a median follow-up of 22.9 months, the median PFS was 22.1 months in the combination arm compared with 16.6 months with placebo plus bevacizumab (HR, 0.59; 95% CI, 0.49-0.72; P < .001).
Among patients with HRD-positive tumors, the median PFS was 37.2 months in the olaparib arm versus 17.7 months in the placebo arm in those with concomitant BRCA mutations (HR, 0.33; 95% CI, 0.25-0.45) and 28.1 months versus 16.6 months, respectively, in those without BRCA mutations (HR, 0.43; 95% CI, 0.28-0.66).14
“We used to follow our patients every 3 months for 2 years because they almost all recur by 2 years. That doesn’t work anymore. Now you need to follow your patients very carefully for a long time because the recurrences have been prolonged: 3 years at the median,” Monk said.
The bevacizumab/olaparib regimen did not raise any significant safety concerns beyond what was expected. “We’re well versed in the use of bevacizumab, and there was no unique toxicity signal seen with that combination,” Powell said. “It is easy to do, and patients tolerate it well. There were at least additive effects for the 2 targeted therapies and maybe even a little more; it’s hard to tell for sure.”
HRD status has recently emerged as a biomarker for ovarian and other cancers. Investigators in the PRIMA and PAOLA-1 trials included HRD status as a marker, but it is still poorly understood. Randall explained that HRD is a phenotypic assay of DNA repair deficiency consisting of 3 components: loss of heterozygosity, telomeric allelic imbalance, and a large-scale state transition.
“Then there is a score of which somatic BRCA is a part. The scoring is complicated, but the cutoff is generally set at 42,” Randall said. That was the cutoff in PRIMA and PAOLA-1, but there is flexibility since that cutoff has not yet been stringently validated, she added.
Randall acknowledged that HRD is not a perfect biomarker but she said HRD status is a helpful measure in the up-front setting.
Monk added, “When I look at PRIMA versus PAOLA-1, 2 very impactful frontline trials, I see there was an impact in the HRP [homologous recombination proficient] group, in other words, the non-HRD group. I didn’t see that in PAOLA-1.”
The panelists surmised that there may be many reasons for the discrepancy between the results.
“The PAOLA-1 patient population is quite different than the population from PRIMA, which had more bad actors. Perhaps you’re seeing a difference that may be statistically significant, but how clinically significant is it, based on the patient population?” Westin asked, noting that the patients in the PAOLA-1 study were getting bevacizumab, a known active drug, and not placebo, which could have had an impact.
Powell said there is no way to know the true effects of these agents in the HRP population and whether one agent is superior to the other without a head-to-head comparison of niraparib and olaparib. “It’s nice that we have an option for PARP inhibition in our proficient patients,” he said. “I’ll leave it at that and say, ‘Thank you, FDA, for giving us some choices.’”