Trial Results Support Front Line Maintenance Treatment With Rucaparib in Ovarian Cancer

At the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting, Pharmacy Times spoke with Bradley Monk, MD, to learn about new results from the ATHENA-MONO trial investigating the use of rucaparib as maintenance treatment following response to front line chemotherapy in patients with ovarian cancer.

Bradley Monk, MD: It's my pleasure to discuss with you today, ATHENA, [or] ATHENA-MONO, sometimes known as GOG-3020 or ENGOT-ov45, which is a randomized, double-blind, phase 3 trial evaluating rucaparib, a PARP inhibitor, as a monotherapy versus placebo as maintenance treatment following response to frontline-based chemotherapy in ovarian cancer. And I'd like to recognize the sponsor, but most importantly thank the patients and their families for this great result.

I think all of you know that frontline maintenance PARP inhibition is here. SOLO-1 got FDA approval in 2018 in BRCA-mutated patients, and then in 2020 we created an all-comer indication with PRIMA for niraparib, and then a bevacizumab [and] olaparib combination restricted to HRD-test-positive individuals. All of those studies have shown an improvement in progression free survival. Clearly the magnitude of the benefit depends on the molecular signature, but the optimal first-line maintenance strategy for treating newly diagnosed advanced ovarian cancer remains unclear, and this trial addresses some of those questions.

Now, ATHENA is 2 integrated, fully powered, randomized phase 3 trials. So, I'm [at ASCO] to present ATHENA-MONO. The second separate trial is ATHENA-COMBO. Now, in ATHENA-MONO, the control arm is placebo with the intervention arm being rucaparib, but in ATHENA-COMBO the intervention arm is the combination of rucaparib 600 mg BID and nivolumab 480 mg IV. So, the eligibility for both ATHENA-MONO and ATHENA-COMBO remained the same: Newly diagnosed stage 3 and 4 high grade epithelial, ovarian, tubal, and peritoneal cancer, who have completed a platinum doublet and are in response, either partial response or complete response with a good performance status of 0 or 1.

Now, the randomization, stratification factors were the HRD molecular status, disease status post-chemotherapy PR or CR, and the timing of surgery—either primary debulking or neoadjuvant. So, the primary endpoint is investigator assessed progression free survival in the HRD test-positive subgroup, which includes not only BRCA-mutated patients, but also those BRCA wild type patients that are LOH-high. And if that met its primary endpoint, which it did, it was stepped down to an intent-to-treat analysis. And then, ultimately, we'll look at overall survival analytically, again in the HRD subset in the third step down and in the fourth intent to treat. And then the fifth is HRD overall response rate and intent to treat overall response rate. The target hazard ratio for the primary first step down was a hazard ratio 0.45—again, which we hit—and 0.60 in the intent to treat—again, which we achieved.

The baseline demographics were well balanced. These are the sorts of patients that you see in your practice, both for the HRD population and the intent to treat population. The stratification factors, of course, were balanced, again, the timing of the surgery on the HRD test and the partial response or complete response. Patients were randomized 4:1 again, 4 to the rucaparib and 1 to the placebo.

The discontinued treatment before 2 years was obviously much higher in the placebo group: 80% versus 63.5%. The number of patients that completed 2 years of protocol rucaparib was 23.7% and in placebo, only 9% made it to 2 years. The discontinuation rate due to adverse reactions was 12.6% in the rucaparib arm. Interestingly, even placebo patients had to discontinue—remember was blinded due to adverse reactions—and that was 5.4%.

So, the primary endpoint was met. The primary endpoint was met in the HRD population, with a hazard ratio of 0.4, more than a doubling of the median. I get it that the median is only one point of the curve, but it helps contextualize the clinical benefit: 11.3 [months] in the placebo arm, [which is] highly consistent with what you would expect, but 28.7 months in the rucaparib group. Again, this was in the HRD subset. The intent to treat analysis was still a hazard ratio of 0.52, and again at the median, it was more than doubling 9.2 to 20.2. Both results were statistically significant, but importantly highly clinically relevant.