August 2020 Edition Vol.11, Issue 8

Making Sense of Maintenance in Ovarian Cancer

By Chase Doyle

The recent FDA approvals of three PARP inhibitors have revolutionized the frontline setting in advanced ovarian cancer, but increased treatment options have also increased the complexity of clinical decision making.

During the ASCO20 Virtual Education Program, Kathleen Moore, MD, Professor of Gynecologic Oncology at the University of Oklahoma Health Sciences Center, summarized the data from three groundbreaking trials to make sense of the new treatment paradigm.1

Before PARP Inhibition

According to Dr. Moore, with the combination of platinum-based chemotherapy and cytoreductive surgery, approximately 80% of women with advanced ovarian cancer finish first-line treatment either in complete response or with no evidence of disease. Unfortunately, within three years, 80% of patients will have experienced disease recurrence.

“Once recurred, there are many therapies that can prolong progression-free survival (PFS) incrementally, but patients are no longer curable,” said Dr. Moore. “Our biggest opportunity to make an impact in the fraction of women that are converted to cures is with frontline therapy.”

While the incorporation of bevacizumab was the first major paradigm shift in front-line ovarian cancer and did impact PFS, “it did not move the needle in terms of percentage of patients who were converted to cures,” said Dr. Moore.

PARP inhibitors, however, are a different story.

SOLO-1 Study

The phase III SOLO-1 study randomized women with BRCA-mutant advanced ovarian cancer, who were in complete or partial response to platinum-based chemotherapy, to olaparib or placebo stratified by response to chemotherapy.2 Study treatment continued until disease progression. Treatment for patients with no evidence of disease was stopped at two years. However, patients with a partial response at two years could continue treatment.

At a median follow-up of 42 months, primary analysis showed a 70% reduction in the risk of disease progression or death with olaparib versus placebo following platinum-based chemotherapy.

“This was an unprecedented improvement in PFS,” said Dr. Moore. “At three years, 60% of women randomized to olaparib were progression free compared to only 27% of those randomized to placebo.”

In addition to bringing genetic testing into the forefront as a must for ovarian cancer, SOLO-1 also shattered the myth that patients with BRCA-associated cancers were all cured with chemotherapy and surgery, said Dr. Moore.

PFS was improved with olaparib in stage III patients who underwent surgery and had no residual disease, a population that has been excluded from a number of contemporary first-line trials.

“This may be the last opportunity to see the impact of an effective therapy in the best prognostic group of advanced ovarian cancer,” said Dr. Moore.

Olaparib was approved for maintenance therapy in BRCA-associated frontline ovarian cancer in December 2018.

PRIMA Trial

The phase III PRIMA trial enrolled patients with newly-diagnosed ovarian cancer at high risk for recurrence after response to first-line platinum-based chemotherapy.3 The trial allowed all comers (patients did not have to be BRCA-mutated) and patients were randomized to niraparib or placebo until disease progression or 36 months.

Patients were stratified by homologous recombination test status: deficient or proficient/not-determined. The study’s primary endpoint was PFS in patients with homologous recombination deficient (HRD) tumors, including BRCA-mutant tumors, followed by the overall population.

More than one third of patients enrolled in PRIMA were stage IV, and nearly 70% of patients received neoadjuvant chemotherapy, said Dr. Moore, who underscored how “incredibly high risk” this population was. Nevertheless, use of niraparib versus placebo led to a 30% reduction in the risk of progression or death in the overall population. Median PFS was 13.8 months for niraparib versus 8.2 months for placebo.

In the HRD population, use of niraparib versus placebo led to a 57% reduction in the risk of progression or death, and PFS improved from 10 to 22 months.

Although not hypothesis tested, niraparib was also associated with a statistically significant improvement in PFS in the highest risk population: patients with non-HRD disease.

Niraparib was approved for first-line maintenance of advanced ovarian cancer regardless of biomarker status on April 29, 2020.

PAOLA-1 Trial

Conducted entirely outside the U.S. where use of bevacizumab with frontline chemotherapy is standard of care, the phase III PAOLA-1 trial randomized women who had a complete response or partial response to first-line platinum-based chemotherapy and bevacizumab to receive olaparib in combination with bevacizumab or bevacizumab with placebo as a first-line maintenance treatment regardless of genetic status or outcome to prior surgery.4 Patients were stratified by BRCA status, and the primary endpoint was PFS.

Use of olaparib in addition to bevacizumab led to a 41% reduction in the risk of progression or death versus bevacizumab maintenance alone in the overall population.

As Dr. Moore reported, the benefit with olaparib was most pronounced in patients with HRD-positive tumors, including tumors that had BRCA mutations. In this subgroup, the median PFS was 37.2 months and 17.7 months with the olaparib combination and bevacizumab alone, respectively.

In those who had HRD-positive tumors without BRCA mutations, the median PFS was 28.1 months with olaparib/bevacizumab and 16.6 months with bevacizumab alone, respectively.

In patients with non-HRD tumors, no difference was observed between study arms.

Olaparib with bevacizumab was approved in patients with HRD-positive tumors on May 8, 2020.

Bevacizumab and Olaparib: New Standard of Care? 

Because the PAOLA-1 trial did not have an olaparib alone arm, a direct comparison between PAOLA-1 and SOLO-1 trials is not possible in BRCA-associated cancer, said Dr. Moore. However, a weighted propensity analysis of the data suggests that if there is a benefit to adding bevacizumab in this population, it’s likely only additive.

“If you feel bevacizumab is indicated in the frontline for a patient because of stage or status of disease and you discover that they have a BRCA-mutated or HRD-positive tumor, this gives you permission to layer on olaparib,” Dr. Moore explained. “In patients who did not start bevacizumab for frontline chemotherapy who are eligible for olaparib maintenance, however, you can opt to do a single agent.”

Dr. Moore doesn’t think this combination sets a new standard of care, but thought it is an option when bevacizumab is already being used, “which is nice,” she added.

For patients who are HRD-positive, Dr. Moore said the decision comes down to whether or not bevacizumab is introduced with frontline chemotherapy, which is one of two potential regimens. For patients with unknown or homologous recombination proficient tumors, on the other hand, data from PRIMA suggest that niraparib is a clinically effective option to consider.

“We don’t know if niraparib is better than bevacizumab in this population,” said Dr. Moore. “That’s the next clinical trial that will need to be run.”

Frontline Ovarian Cancer
Homologous Recombination Proficient • Bevacizumab with and to follow chemotherapy
• Niraparib switch maintenance
• Can consider no maintenance
Homologous Recombination Deficient • Niraparib switch maintenance
• Olaparib + bevacizumab
• Can consider bevacizumab alone
BRCA-Associated Cancers • Olaparib switch maintenance (+/- bevacizumab)
• Niraparib switch maintenance

References

  1. Moore, K. Integration of PARP Inhibitors in Upfront Management of Advanced Ovarian Cancer: Where, When, and Who. Presented at: 2020 ASCO Virtual Education Program; August 8, 2020.
  2. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer [published online ahead of print on October 21, 2018]. N Eng J Med. doi: 10.1056/NEJMoa1810858.
  3. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. Published April 29, 2020. https://bit.ly/3aO6uKP. Accessed April 29, 2020.
  4. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Eng J Med. 2019;381(25):2416-2428. doi: 10.1056/NEJMoa1911361.

Post a Comment

OBR Archives

To view previous issues of OBR green you can visit our archives. The entire library of OBR green articles is searchable.