Switch Maintenance Therapy In Advanced Ovarian Cancer: The ARIEL3 Trial

EP: 1.Case Presentation: A 64-Year-Old Woman With Ovarian Cancer

EP: 2.Role of Molecular Testing in Advanced Ovarian Cancer

EP: 3.Frontline Maintenance Therapy in Advanced Ovarian Cancer

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EP: 4.Switch Maintenance Therapy In Advanced Ovarian Cancer: The ARIEL3 Trial

EP: 5.PARP Inhibitors in Advanced Ovarian Cancer: Mechanism of Action and Tolerability

EP: 6.Considerations for Selecting PARP Inhibitor Maintenance Therapy

EP: 7.Ovarian Cancer: Current Status and Future Directions

Ramez Eskander, MD: ARIEL3 was a prospective randomized clinical trial that took patients who had a high-grade serous or endometrioid ovarian cancer. The trial was designed so that these patients had to have 2 or more prior lines of platinum-containing chemotherapy, and they had to be platinum-sensitive following the penultimate platinum challenge, with a response to therapy. These patients were then randomized after the response to platinum-based combination chemotherapy to rucaparib vs placebo. Rucaparib 600 mg po bid [orally twice a day] vs placebo. And it was a 2:1 randomization, 375 patients were randomized to rucaparib, and 189 patients were randomized to placebo. The primary end point for the study was investigator-assessed progression-free survival [PFS]. And they did a hierarchical analysis where they looked at response rates in the BRCA-mutated patient population, the homologous recombination deficient [HRD] population—interestingly here assessed by loss of heterozygosity alone rather than the HRD biomarker—and then in the intent-to-treat or the all-comer population. And what we see and what’s important to note is that the magnitude of benefit was preserved throughout. The ARIEL3 trial showed a PFS benefit across all prespecified subgroup analyses. The magnitude of benefit was greatest in the BRCA-mutated population, where the progression-free survival difference was 16 months in the rucaparib arm vs 5 months for the placebo arm. There was still a preserved benefit in the homologous recombination deficient cohort, 13 months vs 5 months, and in the entire intent-to-treat population, there was a doubling in the progression-free survival, approximately 10 months vs 5 months.

You can see here in the ARIEL3 clinical trial maintenance with rucaparib as a strategy in patients who respond to their platinum combination therapy resulted in a meaningful progression-free survival benefit across all subgroups, including the intent-to-treat, a proportion of whom were biomarker negative. And this is important and relevant for us because again it highlights how maintenance therapy, or what we can consider switch maintenance therapy, in these patients who have a platinum-sensitive disease recurrence and a response to chemo [chemotherapy], and who didn’t see a PARP inhibitor in the front line, if they were the biomarker-negative patient who may have received bevacizumab, they have the option to do PARP maintenance therapy at platinum-sensitive recurrence.

What’s intriguing is more of these data have emerged, most recently presented at ASCO [American Society of Clinical Oncology 2021 meeting], highlighting that this benefit is preserved beyond the second-line rechallenge, time to second subsequent therapy, time to disease recurrence after rechallenge, second PFS, all were meaningfully prolonged in the patients who received rucaparib vs placebo in the ARIEL3 trial. The other interesting finding was an abstract that looked at exceptional responders, patients who were on treatment for greater than 2 years. And although those exceptional responders were enriched for in the BRCA-mutated or the homologous recombination deficient patient population, there were also patients who were biomarker negative who were exceptional responders. That speaks to the fact that we don’t yet have a perfect biomarker to predict response to PARP maintenance therapy, and it should be considered in these platinum-sensitive recurrent patients because you may have an exceptional responder in the context of a patient who was biomarker negative. That’s an opportunity that we wouldn’t want to pass over in a difficult to treat disease.

This transcript has been edited for clarity.

Case:A 64-Year-Old Woman With Ovarian Cancer

Initial Presentation

• A 64-year-old woman presented with abdominal bloating, low back pain, early satiety and progressive fatigue
• PMH: hysterectomy 5 years ago for benign indication; hypothyroidism managed medically; generalized anxiety disorder managed medically
• PE: diffuse lumbosacral pain with movement; abdominal tenderness and significant abdominal distension with a fluid weight consistent with ascites; unintentional weight loss of 8 lbs
• ECOG PS 1

Clinical work-up

• Pelvic ultrasound showed a ~5-cm complex left ovarian mass
• Chest/abdomen/pelvis CT revealed a complex pelvic mass and was also notable for abdominal ascites, omental cake, and retroperitoneal and inguinal adenopathy
• Paracentesis (1200cc) cytology confirmed high-grade serous ovarian cancer
• Omental biopsy histology also confirmed high-grade serious ovarian cancer
• Germline molecular testing: BRCA1/2wt
• Somatic testing: BRCA1/2 negative; HRD proficient
• CA-125, 360 U/mL
• Diagnosis: Stage III, high-grade serous epithelial ovarian cancer

Treatment

• Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0
  • Carboplatin/paclitaxel q3 weeks for 6 cycles; CA-125 normalized; CR
  • Bevacizumab maintenance
• At 1 year post treatment, CA-125 increased; imaging revealed progressive retroperitoneal adenopathy suggestive of recurrent disease; not deemed a candidate for secondary surgery
  • Rechallenged with carboplatin/paclitaxel q3 weeks for 6 cycles; PR; predominantly enlarged lymph nodes
  • Rucaparib monotherapy maintenance