“Durvalumab and olaparib [given] concurrently with paclitaxel increased pCR rates in all 3 biomarker subsets where it was studied. The estimated probability that the experimental arm is superior to chemotherapy alone is greater than 98% in all subsets.”
Adding durvalumab (Imfinzi) and the PARP inhibitor olaparib (Lynparza) to treatment of neoadjuvant paclitaxel led to improved pathologic complete response (pCR) rates in patients with high-risk, HER2-negative stage II/III breast cancer compared with single-agent paclitaxel, according to the phase II I-SPY 2 study presented at the 2020 Annual AACR Virtual Meeting.1
Data showed that in all patients with HER2-negative breast cancer, the predicted probability of pCR with the combination and with paclitaxel alone was 37% (95% CI, 0.27-0.47) and 20% (95% CI, 0.16-0.25), respectively. When broken down by subset, the respective pCR rates were 28% (95% CI, 0.18-0.38) versus 14% (95% CI, 0.09-0.19) in patients with hormone receptor (HR)–positive disease. In those with triple-negative breast cancer (TNBC), the pCR rate was 47% (95% CI, 0.29-0.64) with the combination and 27% (95% CI, 0.20-0.34) with chemotherapy alone.
Moreover, there were no unexpected safety signals; the adverse events (AEs) were consistent with the known safety profiles of each agent alone.
“Durvalumab and olaparib [given] concurrently with paclitaxel increased pCR rates in all 3 biomarker subsets where it was studied,” lead study author Lajos Pusztai, MD, DPhil, professor of medicine (medical oncology) and co-leader of Genetics, Genomics, and Epigenetics at Yale Cancer Center, said in a virtual presentation during the meeting. “The estimated probability that the experimental arm is superior to chemotherapy alone is greater than 98% in all subsets.”
The rationale to combine checkpoint inhibitors with PARP inhibition is partly biologic, Pusztai said, explaining that impaired nucleotide and base excision repair increase mutation and neoantigen load, and DNA fragments activate the intracellular STING pathway. Also, PARP inhibition upregulates PD-L1 expression in breast cell lines.
Previously, results of the open-label phase 1/2 basket MEDIOLA (NCT02734004) trial showed that the combination of olaparib and durvalumab had clinical activity in a cohort of patients with germline BRCA-mutated metastatic breast cancer.2 The objective response rate was 63.3% with the combination in this patient population. Another phase 2 trial (NCT03801369) of olaparib and durvalumab in patients with BRCA wild-type metastatic TNBC is ongoing.
The I-SPY 2 trial is designed as a multicenter, phase 2 neoadjuvant study that uses response-adaptive randomization with multiple concurrent experimental arms and a shared control arm. Overall, the design is based on Bayesian predictive probability that a biological regimen will be shown to be statistically superior to standard treatment in an equally randomized 300-patient confirmatory trial.3 Regimens that demonstrate a high Bayesian predictive probability of showing superiority in ≥1 of 10 predefined signatures then graduate from the I-SPY 2 study.
However, regimens are dropped for futility if they show a low predictive probability of showing superiority over standard therapy in all 10 signatures, and up to 120 patients can be assigned to each experimental regimen.
For this particular arm of the I-SPY 2 trial, investigators sought to determine whether the neoadjuvant combination of olaparib, durvalumab, and paclitaxel would increase pCR rates compared with chemotherapy alone in HER2-negative biomarker subgroups of patients with stage II/III breast cancer. The biomarker subsets included: all patients with HER2-negative breast cancer, those with HR-positive/HER2-negative disease, and TNBC.
To be eligible for enrollment on the study, patients must have had a tumor size ≥2.5 cm, agree to undergo MRI and biopsy, have adequate organ function, and an ECOG performance status <2. If patients had HR-positive disease, they needed to have a high MammaPrint score.
Patients received either paclitaxel alone at 80 mg/m2 weekly for 12 cycles (n = 299) or in combination with 1500 mg of durvalumab every 4 weeks for 3 cycles, plus olaparib at 100 mg twice daily for weeks 1 to 11 (n = 73). Prior to surgery, all patients received doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 for 4 cycles, which was given every 2 or every 3 weeks.
The primary end point of the trial is pCR; graduation was based on the pCR for patients who underwent surgery and MRI response over time for patients still on treatment. Investigators determined that in order for the combination regimen to be studied in a future phase 3 trial, the graduation for efficacy was a ≥85% predicted probability of success with the combination over standard therapy. If the probability of success dropped <10%, then the trial was stopped for futility. The maximum accrual reached was 75 patients overall with HER2-negative breast cancer.
The median age of patients enrolled on the trial was 47 years; 79.5% were white, 12% were African American, 7.5% of patients were Asian, and 0.5% of patients were reported as other. Additionally, 62% of patients had HR-positive disease and 38% had HR-negative disease; specifically, in the combination arm, 71% and 29% of patients had HR-positive and HR-negative disease, respectively. The median tumor size was similar between the combination and control arms, at 3.7 cm and 3.8 cm, respectively. Moreover, overall, 32.5% of patients had palpable nodes.
Additional results also demonstrated the probability that the experimental regimen is superior to the control arm and the predicted probability of success in a 300-patient randomized trial. In all patients with HER2-negative breast cancer, the probability that olaparib/durvalumab plus chemotherapy is superior to the control arm was 99.9% and the probability of success in a phase 3 trial was 81.4%.
In the TNBC subset, the probability rate that the combination is superior to the control arm was 98.4%, with an 80.6% rate that it will be successful in a phase 3 study. Finally, in the HR-positive/HER2-negative group, the probability success rate versus the control arm was 99.6%; the rate of succeeding in a phase 3 trial was 74.5%.
Moreover, the combination was found to shift residual cancer burden (RCB) to lower values across all RCB categories across subtypes, except for RCB-III in patients with TNBC.
“Durvalumab and olaparib not only increased the rate of pCR, it also shifted RCB categories toward lower values,” Pusztai explained. “In other words, there were also fewer RCB-II and RCB-III patients in the experimental arm, indicating smaller residual cancers across the entire residual disease spectrum.”
Regarding safety, adverse events (AEs) were reported in 43 patients in the durvalumab/olaparib arm compared with 251 patients who received chemotherapy alone, as of March 15, 2020. The rate of grade 3/4 AEs occurred in 58% and 41% of patients on the experimental and control arms, respectively. The most frequent grade 3/4 AEs experienced in the combination arm and the paclitaxel-alone arm, respectively, included febrile neutropenia (16.3% vs 8.4%), colitis (7% vs 0.4%), adrenal insufficiency (7% vs 0%), increase in alanine aminotransferase levels (4.7% vs 2%), dehydration (4.7% vs 0.8%), and vaginal infection (4.7% vs 0%).
Immune-related AEs of special interest also occurred. Nineteen percent of patients on durvalumab/olaparib experienced grade 3 immune-related AEs versus 1.6% of those on the chemotherapy-alone arm; these events included colitis (n = 3), adrenal insufficiency (n = 3), pancreatitis (n =1), and thyroiditis (n = 1).
When exploring pre-specified predictive markers, investigators also noted that higher expression of most immune markers were associated with higher pCR rates across both arms, and there was no significant marker-treatment interaction. Furthermore, in the HR-positive/HER2-negative subtype, patients with an ultra-high MammaPrint score (MP2; n = 77) was found to have the most benefit from the combination, with an estimated pCR rate of 64% compared with a 22% pCR rate in the control arm. In patients with an MP1 score (n = 132), the estimated pCR rate was 9% with olaparib/durvalumab versus 10% with the control.
In the TNBC subset, low CD3/CD8 gene signature ratio, high macrophage/Tc-Class 2 ratio, and high proliferation signatures were associated with a higher pCR in the combination arm versus the control arm.
As a discussant during the presentation, Pamela Munster, MD, a professor in the Department of Medicine (Hematology/Oncology), University of California, San Francisco; director of the Early Phase Clinical Trials Unit, co-leader of the Center for BRCA Research; and leader of the Experimental Therapeutics Program at UCSF Helen Diller Family Comprehensive Cancer Center, shared her insight on where this combination may fit best for this patient population.
“What we know so far in preoperative therapy for breast cancer is that pCR is associated with better outcomes,” Munster said. “What we learned together from Dr. Pusztai's presentation is that there may be promising activity with olaparib and durvalumab in addition to paclitaxel. This combination may be of particular interest to a subgroup of women with tumors expressing ultra-high MammaPrint. The toxicity, as presented today, appears incomplete, and one should consider the financial toxicity from this combination."