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Anti-PD-L1 Plus PARP Inhibitor Ups Response in Breast Cancer

— Add-on treatment superior to chemo alone, but questions remain about cost, toxicity

MedpageToday

The rate of pathologic complete response (pCR) increased significantly in patients with high-risk HER2-negative breast cancer treated preoperatively with durvalumab (Imfinzi) and olaparib (Lynparza) in addition to chemotherapy, a phase II randomized trial showed.

Overall, 37% of patients attained a pCR with durvalumab, olaparib, and chemotherapy as compared with 20% for chemotherapy only. Among patients with triple-negative breast cancer (TNBC), the addition of durvalumab and olaparib improved pCR from 27% with chemotherapy alone to 47%. Patients with hormone receptor (HR)-positive disease had a pCR rate of 28% with durvalumab and olaparib versus 14% with chemotherapy only.

No unexpected toxicities occurred, but more patients in the durvalumab-olaparib arm had grade 3 immune adverse events (AEs), reported Lajos Pusztai, MD, of the Yale Cancer Center in New Haven, Connecticut, at the American Association for Cancer Research (AACR) virtual meeting.

"Durvalumab plus olaparib increase the pCR rates in all three biomarker subsets," he said. "There were no unexpected safety signals, and adverse events were consistent with the known side effects. Immune-rich cancers showed higher pCR rates in all subtypes and in both treatment arms."

The findings came from the , which evaluates the potential of novel agents and combinations as neoadjuvant therapy for breast cancer. Several lines of evidence provided a rationale for investigating a PD-1/L1 inhibitor and a PARP inhibitor, said Pusztai. DNA repair deficiency in cancer cells can induce production of immunogenic neoantigens, activation of the stimulator of interferon genes pathway, and upregulation of PD-L1 expression.

Eligibility criteria included newly diagnosed HER2-negative breast cancer and tumor size ≥2.5 cm. Patients with HR-positive breast cancers had to have a high-risk molecular profile by the MammaPrint assay. Patients received 12 weeks of treatment with durvalumab, olaparib, and paclitaxel, followed by four cycles of doxorubicin/cyclophosphamide chemotherapy. The control group received only the chemotherapy.

The primary endpoint was pCR (ypT0/is and ypN0). Patient accrual to the experimental arm continued to a maximum of 75 patients. According to the I-SPY 2 protocol, a regimen "graduates with success" when the Bayesian predictive probability of success in a 300-patient phase III neoadjuvant trial reaches ≥85%. Graduation occurs whenever the probability reaches the 85% threshold, although follow-up for efficacy (including MRI) continues.

In the evaluation of durvalumab and olaparib, graduation to eligibility for a phase III trial required reaching the 85% threshold in the overall population and in the biomarker-defined subgroups of TNBC and HR-positive/HER2-negative breast cancer. The trial reached the graduation efficacy threshold after 73 patients in the experimental arm had undergone surgery.

Patients in the experimental arm had a median age of 46 as compared with 48 in the control arm. Pusztai said 52 of 73 patients treated with durvalumab and olaparib had HR-positive breast cancer and 21 had HR-negative.

The data showed with near-100% probability that the addition of durvalumab and olaparib resulted in superior treatment versus chemotherapy alone with respect to achieving pCR in the three specified biomarker groups: 99.9% for all HER2-negative patients, 98.4% for the TNBC subgroup, and 99.6% for the HR-positive subgroup. The final predicted probability of success in a 300-patient randomized trial was 81.4% overall, 80.6% for the TNBC subgroup, and 74.5% for the HR-positive subgroup.

Beyond pCR, treatment with durvalumab and olaparib shifted residual cancer burden (RCB) to lower values versus the control group across all RCB categories except RCB III in the TNBC subgroup.

More patients in the experimental arm had grade 3/4 AEs than in the control arm (58% vs 41%). Notable differences included febrile neutropenia (16.3% vs 8.4%), colitis (7% vs 0.4%), adrenal insufficiency (7% vs 0%), increased ALT (4.7% vs 2%), dehydration (4.7% vs 0.8%), and vaginal infection (4.7% vs 0%).

Data for 43 evaluable patients in the experimental arm showed a 19% incidence of immune-related toxicities, consisting of three cases each of colitis and adrenal insufficiency and one each for pancreatitis and thyroiditis. No immune-related events occurred among patients treated with chemotherapy alone.

AACR invited discussant Pamela Munster, MD, of the University of California San Francisco, said the study added to what was already known about neoadjuvant therapy for breast cancer. The experimental arm increased the pCR rate, and pCR is clearly associated with better outcomes. High PD-L1 expression has been reported in early-stage TNBC, and PD-1/L1 is associated with a higher response to immune checkpoint plus chemotherapy, as well as chemotherapy alone. PARP inhibitors have shown promising single-agent activity in BRCA-mutant tumors.

The addition of durvalumab and olaparib to paclitaxel had promising activity, and the study suggested the potential to pre-select patients with high-risk HR-positive breast cancer by use of the MammaPrint assay. However, she noted that immunotherapy alone has demonstrated promising activity in HER2-negative breast cancer, raising questions about the value of adding a PARP inhibitor.

"The toxicity appears incomplete [particularly olaparib-associated toxicity], and we must consider the financial toxicity of adding durvalumab and olaparib to the treatment," said Munster. "The contribution of PARP inhibitors to immunotherapy in early-stage breast cancers remains uncertain. We are awaiting confirmatory randomized studies that are stratified for PD-L1 expression, BRCA mutation, and homologous recombination deficiency."

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

I-SPY 2 trials are supported by the .

Pusztai disclosed relevant relationships with AstraZeneca, Merck, Novartis, Bristol-Myers Squibb, Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Clovis, Syndax, H3Bio, and Daiichi Sankyo.

Primary Source

American Association for Cancer Research

Pusztai L, et al "Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2-negative stage II/III breast cancer: Results from the I-SPY 2 trial" AACR 2020; Abstract CT011.