Rucaparib Explored for High-Risk Ovarian Cancer

Ramez N. Eskander, MD: ARIEL2 Part 1 was an important trial. It was an informative trial not just because of the outcomes data when you look at median progression-free survival in the cohorts, but it also took a purposeful assessment of a biomarker, specifically loss of heterozygosity [LOH], and looked at the implications on treatment response. That’s specifically looked at in ARIEL2 Part 1.

This was an international multicenter 2-part phase 2 trial. A total of 206 patients were enrolled on that trial between 2013 and 2014. And when we look at these patients in Part 1, they were defined to be recurrent platinum-sensitive patients.

So we were looking at platinum-sensitive patients, and we split them into 3 cohorts. We looked at patients who had a BRCA mutation, either germline, inherited; or somatic, acquired. We looked at patients who had an LOH-high score as well as a cohort of patients who had an LOH-low score. Importantly, for ARIEL2 Part 1, the LOH cutoff of 14% was derived from a retrospective analysis of data from the TCGA [The Cancer Genome Atlas] study. That 14% cutoff was subsequently incorporated into the clinical trial, and it was used as a way to stratify these patients.

And what we saw, if you looked at the 3 cohorts who were exposed to rucaparib given at 600 mg orally twice a day, was the median progression-free survival in the BRCA mutation population was 12.8 months. The median progression-free survival in the LOH-high population was 5.7 months. In the LOH-low population, it was 5.2 months. There was a significant improvement in the median progression-free survival for both the BRCA-mutated population and the LOH-high population when compared to the LOH-low population.

And in parallel, from the ARIEL2 Part 1 study, we saw that the median duration of response was also significantly higher in the BRCA-mutated and LOH-high versus LOH-low groups, and that was 9.2 months versus 10.8 months in the LOH-high population. In the LOH-low population, it was 5.6 months. And something that I think is important to look at from the ARIEL2 Part 1 study was that they evaluated the patients with germline and the somatic BRCA mutations and looked at the response in these 2 populations. What they saw was a similar response in patients with germline or somatic BRCA mutations, suggesting that whether it’s an inherited mutation in the germline or an acquired mutation in the tumor, the anticipated response to rucaparib and the magnitude of benefit is similar.

This study was very informative because it helped us learn more about the relevance of loss of heterozygosity, especially with respect to monotherapy PARP inhibition with rucaparib given at 600 mg twice a day. And in parallel, it also helped us try to refine this loss of heterozygosity cutoff score. As many may be aware, when ARIEL3 was designed, that LOH cutoff transformed from 14% to 16%. That was based on a retrospective assessment of the data from ARIEL2 Part 1.

ARIEL2 Part 2 is a slightly different trial. ARIEL2 Part 2 is specifically looking at an all-comers population. Patients are platinum-sensitive, platinum-resistant, or platinum-refractory. The investigators are looking at response to treatment with rucaparib. What’s going to be informative about ARIEL2 Part 2 when those data emerge is, how can we expand the patient population that may benefit beyond the platinum-sensitive disease recurrence that was reported in ARIEL2 Part 1? We await the results of ARIEL2 Part 2, but the hope is that we have therapeutic options available for more of our patients based on efficacy data from these trials.

Transcript edited for clarity.

Case: A 71-Year Old Woman With High-Risk Ovarian Cancer

Initial presentation

• A 71-year old woman presented to her PCP for a routine annual checkup, she complains of increasing fatigue
• PMH:
  • Hypertension, controlled on a thiazide
  • 2017 diagnosed with stage IV ovarian cancer; BRCAwt; underwent TAH/BSO, lymph node dissection, with suboptimal debulking; treated with paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab; achieved CR

Currently

• CA-125, 456 U/mL
• Chest/abdomen/pelvis CT with contrast shows a suspicious lung lesion
  • Lung biopsy confirmed recurrent epithelial ovarian cancer
• Molecular testing showed HRD+, LOH high
• ECOG: 0

Treatment and Follow-Up

• She was started referred to an oncologist and started on carboplatin/doxorubicin, treatment was well tolerated for 4 cycles; CA-125 35 U/mL;
  • Rucaparib 300 mg BID maintenance was initiated
• At 2 months follow-up
  • CA-125 was undetectable
  • Chest/abdomen/pelvis CT showed no gross masses or nodes
  • Pelvic exam was unremarkable