No Clinical Benefit in rOC With Atezolizumab Plus Chemotherapy
There was no statistically significant improvement in clinical outcomes (including progression-free survival [PFS] and objective response rate [ORR]) observed in patients with recurrent ovarian cancer (rOC) treated with atezolizumab (Tecentriq) in addition to chemotherapy and niraparib (Zejula) maintenance therapy, according to findings from the phase 3 ANITA trial (NCT03598270) presented during the 2023 ESMO Annual Congress.
At a median follow-up of 36 months, patients who received the PD-L1 inhibitor in addition to chemotherapy with a carboplatin-containing doublet and maintenance (n = 208) experienced a median PFS of 11.2 months (95% CI, 10.1-12.1) compared with 10.1 months (95% CI, 9.2-11.2) among patients who were treated with placebo in place of atezolizumab (n = 209; HR, 0.89; 95% CI, 0.71-1.10; P = .28). Moreover, no significant PFS benefit was observed with the addition of atezolizumab among patients with PD-L1-positive disease (HR, 0.87; 95% CI, 0.61-1.25), PD-L1-negative disease (HR, 0.93; 95% CI, 0.70-1.24), or those with PD-L1 non-informative status (HR, 1.06; 95% CI, 0.50-2.25). The study missed its primary end point of investigator-assessed PFS.
“Despite strong preclinical rationale, previous phase 3 trials have shown no benefit from the addition of a PD-L1 inhibitor to chemotherapy plus or minus bevacizumab [Avastin] for patients with newly diagnosed or recurrent ovarian cancer,” Antonio Gonzalez-Martin, MD, PhD, the director of the Department of Medical Oncology, a specialist in medical oncology and the director of the Cancer Center Clínica Universidad de Navarra in Madrid, Spain, as well as the president of the Spanish Ovarian Cancer Group (GEICO), said during the presentation. “The [phase 3] DUO-O trial [NCT03737643] showed an improved PFS with the addition of durvalumab plus olaparib [Lynparza] to frontline chemotherapy plus bevacizumab in patients with non-tBRCA-mutated advanced ovarian cancer. [However], the contribution of a PARP inhibitor plus a checkpoint inhibitor with or without bevacizumab remains unknown. ANITA is the first reported phase 3 study evaluating an immune checkpoint inhibitor with platinum chemotherapy plus PARP inhibitor maintenance in late-relapsing rOC.”
ANITA was a multicenter study that enrolled patients with high-grade serous, endometrioid, or undifferentiated rOC with an ECOG performance status of 1 or less. To be included in the study, patients needed to be immune checkpoint inhibitor naïve and have aplatinum therapy-free interval of more than 6 months. Patients were permitted to receive up to 2 prior lines of chemotherapy and a mandatory de novo biopsy was also required. Prior treatment with a PARP inhibitor for rOC was not allowed.
Eligible patients were randomly assigned 1:1 to receive either atezolizumab or placebo plus chemotherapy for 6 cycles. After this, atezolizumab 1200 mg or placebo on day 1 plus niraparib at an individualized starting dose on days 1 through 21 every 21 days was given as maintenance therapy until disease progression (PD). Patients were stratified by carboplatin doublet (PLD vs gemcitabine vs paclitaxel), platinum therapy-free interval (6-12 months vs > 12 months), BRCA status (mutated vs non-mutated), and PD-L1 status (IC < 1% vs ≥ 1% vs non-informative).
The data cutoff for the primary end point was April 15, 2023, and the target HR was 0.70. Secondary end points included objective response rate (ORR), overall survival, PFS from the start of maintenance, safety, and patient-reported outcomes among others.
The baseline patient characteristics were generally well balanced between the atezolizumab and placebo arms; the median age was 63 years (range, 37-85) compared with 62 years (range, 23-82), respectively. Most patients in both arms had an ECOG performance status of 0 (64% vs 60%), high-grade serous histology (89% vs 92%), had undergone 1 prior line of therapy (87% vs 86%), had PLD in their chemotherapy backbone (71% vs 72%), and had a platinum therapy-free interval of over 12 months (65% vs 67%). A majority of patients in both arms also had negative PD-L1 status (56% vs 54%) and did not have BRCA-mutated disease (87% vs 85%).
Additional data demonstrated that patients in the atezolizumab arm experienced an ORR of 45% (95% CI, 39%-52%) during chemotherapy compared with 43% (95% CI, 36%-49%) in the placebo arm. Patients in both arms experienced complete responses (7% vs 6% respectively) and stable disease (44% vs 46%).
Fifty-seven patients in the atezolizumab arm did not start maintenance therapy, due to PD (n = 42), death (n = 3), toxicity (n = 4), withdrawal (n = 4), and other reasons (n = 4). In the placebo arm, 53 patients did not start maintenance due to PD (n = 37), death (n = 5), toxicity (n = 3), withdrawal (n = 4), and other reasons (n = 4). The median PFS from the start of maintenance was 6.7 months (95% CI, 5.3-8.3) vs 5.3 months (95% CI, 4.3-6.1) in the atezolizumab (n = 150) and placebo (n = 156) arms, respectively (HR, 0.80; 95% CI, 0.62-1.03).
In the PFS subgroup analysis, the only patients who experienced a significant PFS benefit with the addition of atezolizumab were those with non-mutated BRCA status (HR, 0.79; 95% CI, 0.63-0.99) and those whose chemotherapy backbone contained gemcitabine (HR, 0.54; 95% CI, 0.31-0.94). All other subgroups either experienced a non-statistically significant benefit with atezolizumab or displayed PFS findings that favored the placebo arm.
In terms of safety, any-grade adverse effects (AEs) occurred in 97% of patients in both the atezolizumab and placebo arms. Patients in both arms experienced grade 3 or higher treatment-related AEs (TRAEs; 65% vs 63% respectively), serious AEs (37% vs 30%), immune-mediated AEs (23% vs 9%), and AEs leading to niraparib dose reduction (49% vs 43%). Two patients in the atezolizumab arm experienced grade 5 TRAEs.
The most common non-hematological any-grade AEs observed during the chemotherapy phase in both the atezolizumab and placebo arms were asthenia, nausea, and constipation; these were also the most common in both arms during the maintenance phase. During the chemotherapy phase, approximately 60% of patients experienced anemia and neutropenia in the placebo arm compared with approximately 45% and 55%, respectively, in the atezolizumab arm.
“The safety profile was predictable and manageable and no new safety signals with atezolizumab in combination with chemotherapy and maintenance niraparib were observed,” Gonzalez-Martin said. “Survival follow-up as well as other secondary end points and biomarker research is still ongoing. We can conclude that ANITA provides relevant information for the interpretation of other phase 3 trials with checkpoint inhibitors and PARP inhibitors in ovarian cancer.”
