Rucaparib Maintenance Therapy in Ovarian Cancer: The ARIEL3 Trial

EP: 1.Case Presentation: A 57-Year-Old Woman With Ovarian Cancer

EP: 2.Molecular Testing: Ovarian Cancer

EP: 3.First-Line Therapies in Ovarian Cancer

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EP: 4.Rucaparib Maintenance Therapy in Ovarian Cancer: The ARIEL3 Trial

EP: 5.Toxicities With PARP Inhibitors for Ovarian Cancer

EP: 6.Future Treatments in Ovarian Cancer

Lyndsay Willmott, MD: The ARIEL3 trial was a large clinical trial looking at patients with platinum-sensitive recurrent ovarian fallopian tube or primary peritoneal carcinoma. These patients received platinum-based cytotoxic chemotherapy and then were candidates for enrollment on the trial if they had at least partial response to their platinum-based chemotherapy. The patients who enrolled on this trial could enroll regardless of BRCA mutational status. In other words, all comers were eligible for enrollment. That would include patients with a BRCA mutation of the germline or somatic BRCA mutation, patients who had homologous recombination deficiency by virtue of loss of heterozygosity, and patients who were without evidence of homologous recombination deficiency—in other words, patients who were homologous recombination proficient.

All patients were able to enroll and were randomized to receive either rucaparib at the standard starting dose of 600 mg by mouth twice daily or placebo. These patients were subsequently followed until evidence of disease progression or course-prohibitive toxicity. The primary outcome from this clinical trial is progression-free survival. It was done in an interesting trial design of a nested cohort. The initial cohort that was assessed were patients who had a BRCA mutation. If there was a signal in that population, which there was, it then opened up to include patients with a BRCA mutation and presence of loss of heterozygosity. The third cohort included those 2 first cohorts as well as those patients who were homologous recombination proficient. Then the outcomes assessed all the patients: the large intent to treat group along with these subgroup analyses of these various cohorts.

The outcome from the trial showed that there was very profoundly statistically significant improvement in progression-free survival among all the groups. The most profound was seen in patients with a BRCA mutation, which could include either germline or somatic. The second cohort—those patients with a BRCA mutation and presence of homologous recombination deficiency—had slight diminishment because of high loss of heterozygosity but still very profound improvement in their progression-free survival.

And then that final cohort, which included patients who are homologous recombination proficient, also had slight diminishment but still profound improvement in progression-free survival that favored randomization to the rucaparib arm. What this is saying and what subsequently occurred is that all patients, regardless of BRCA status, are candidates for consideration for rucaparib monotherapy after you finished your platinum-based cytotoxic chemotherapy, along with patients with a platinum-sensitive recurrence, as long as they’ve had at least a partial response to their platinum-based chemotherapy.

We recognize that homologous recombination deficiency is a very important characteristic in the development of ovarian cancer. This leads to problems with the repair of double-stranded DNA breaks. And when you have an accumulation of double-stranded DNA breaks, this leads to genomic instability and the subsequent development of malignancy. When we recognize their inherent problems with the way that ovarian cancer cells can fix their DNA, perhaps we can take advantage of that. That’s this concept of synthetic lethality.

PARP inhibitors work by impairing PARP enzymes, poly [ADP-ribose] polymerase. PARP enzymes are responsible for repairing single-stranded DNA breaks. If we can impair the functionality of that enzyme, or we can perhaps bind that enzyme to the DNA, then that leads to an accumulation of single-stranded DNA breaks. Over time, if those aren’t being repaired, then they can turn into double-stranded DNA breaks. In patients who lack the ability to appropriately repair their double-stranded DNA breaks, they subsequently have overwhelming accumulation of errors and the cells die. This is taking advantage of an underlying impairment in the cancer cell that has led to development of cancer but using it to our advantage.

The ARIEL3 trial confirmed our understanding of PARP inhibition in ovarian cancer. It’s an important trial that demonstrates that patients may be candidates for PARP inhibition regardless of certain types of testing in the recurrent setting. In other words, because of this nested trial design, we’d be able to see if there are only particular patient populations that benefit, and we saw that it appears that all comers benefit. What’s the shared thing that these patients had? This was platinum sensitivity. Platinum sensitivity, in and of itself, is absolutely a biomarker for how patients may respond to PARP inhibition and maintenance.

Obviously, the goal is to push out our platinum-free interval. When we look at the control population from the ARIEL3 trial—those patients who are randomized to placebo—among all these nested cohorts, the median progression-free survival in the patients who are randomized to receive placebo was less than 6 months. When patients are having a recurrence less than 6 months from the completion of their platinum, they are deemed platinum resistant. A platinum-resistant phenotype is a much more complicated phenotype to treat. Unfortunately, there are fewer agents available, and the likelihood of response is poor. Our goal is to try our hardest to maintain platinum sensitivity. If we understand that patients who have a platinum-sensitive recurrence and have responded to their platinum may subsequently be placed onto a PARP inhibitor—in this circumstance, rucaparib based on the ARIEL3 trial—then hopefully they’ll have significant lengthening of their progression-free survival, enabling them to remain in this platinum-sensitive category. Perhaps at the time of recurrence, it will allow us to subsequently re-expose them to platinum.

There are several options for PARP inhibitor maintenance in the recurrent setting. With rucaparib, the ARIEL3 trial has a unique design. There are a large number of patients who were randomized in this trial. Rucaparib itself is a twice-a-day medication. The dosing strategy for rucaparib is different from other PARP inhibitors. There’s a lot more room for a dose modification as necessary. In general, when we start patients on PARP inhibitor maintenance following a platinum sensitive recurrence, that PARP inhibitor is continued until disease progression or prohibitive toxicity. We want to make sure we’re managing toxicities quickly so patients can hopefully stay on these medications for a very long time.

With rucaparib, there’s significant room for dose-reduction strategies. With these dose reductions, we’re not causing huge reductions in the actual amount of dose delivered. The standard starting dose for rucaparib is 600 mg by mouth twice daily. The first dose reduction is to 500, then 400, then 300 mg twice daily. There are multiple levels of dose reductions available, which allows for some degree of flexibility with patient care and is perhaps different from other PARP inhibitors that are available.

Case Overview: A 57-Year-Old Woman With Ovarian Cancer

Initial Presentation

A 57-year-old woman presented with progressive abdominal discomfort and bloating, early satiety, new-onset constipation, and unintentional weight loss

PMH: postmenopausal; hypertension—medially controlled; osteoarthritis

PE: right lower quadrant tenderness on palpation

ECOG PS 1

Clinical work-up

Pelvic exam with ultrasound showed a ~4.5-cm right ovarian mass

Chest/abdomen/pelvis CT with contrast revealed a right adnexal mass with lymph node involvement and ascites

Paracentesis (1200cc) cytology confirmed high-grade serous epithelial ovarian cancer

Germline molecular testing: BRCA1/2wt

Somatic testing: BRCA1/2 negative; HRD positive

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/docetaxel q3 weeks for 6 cycles; CA-125 normalized; CR

Bevacizumab maintenance

At 2 years post chemotherapy, patient experienced abdominal bloating and pain, nausea and vomiting and progressive fatigue; CA-125 increased; imaging revealed progressive retroperitoneal adenopathy suggestive of recurrent disease; not deemed a candidate for secondary surgery

Rechallenged with carboplatin/docetaxel q3 weeks for 6 cycles; PR; predominantly enlarged lymph nodes

Rucaparib single-agent maintenance 600 mg bid

Patient developed clinically significant thrombocytopenia; dose reduced to 500 mg and patient remained on treatment until disease progression

Transcripts edited for clarity.