Olaparib/Durvalumab/Fulvestrant Combo Meets PFS End Point in HRR-Altered or MSI ER+/HER2– Breast Cancer

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The combination of olaparib (Lynparza), durvalumab (Imfinzi) and fulvestrant (Faslodex) demonstrated clinical activity and an acceptable toxicity profile when administered as a second- or third-line treatment to patients with primarily pretreated, endocrine-resistant estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer who expressed molecular abnormalities associated with PARP inhibitor sensitivity, according to data from the randomized phase 2 DOLAF study (NCT04053322).¹

Findings presented during the 2024 ESMO Breast Cancer Congress showed that the progression-free survival (PFS) rate with the triplet at 24 weeks was 66.7% (95% CI, 58.6%-74.1%), meeting the study’s primary end point. The median PFS was 9.3 months (95% CI, 7.5-12.7), and the median overall survival (OS) was 30 months (95% CI, 26.6-not reached [NR]). The overall response rate (ORR) in the entire study population was 41% (95% CI, 33.5%-49.3%), comprising a 16.7% complete response (CR) rate. The median duration of response (DOR) was 12.1 months (95% CI, 6.8-18.4), and 20.9% of patients remained on treatment at the time of analysis. The median follow-up for the overall population was 24.6 months (95% CI, 19.3-28).

In the previously documented germline BRCA-mutant population, the 24-week PFS rate was 76.3% (95% CI, 63.4%-86.4%), with a median PFS of 12.6 months (95% CI, 8.2-16.7). Patients in this cohort achieved an ORR of 57.1% (95% CI, 44%-69.5%), including a CR rate of 19.4%, a median OS of 29.3 months (95% CI, 22.2-NR), and a median DOR of 13.3 months (95% CI, 5.8-NR). The median follow-up for this cohort was 16.6 months (95% CI, 13.1-23.2).

“In our previously documented germline BRCA-mutant population our results are particularly striking…suggesting that ER signal inhibition remains important for these patients in addition to PARP inhibitor and immune checkpoint inhibitor [exposure],” lead study author Séverine Guiu, MD, PhD, a breast cancer specialist and head of the Medical Oncology Department at the Montpellier Cancer Institute in France, explained in an oral presentation. “Our results compare well with current standards in the second- and third-line settings, including in the non-germline BRCA-mutant population, particularly in the case of homologous recombination repair [HRR] alterations.”

Further assessment of other subgroups of interest demonstrated no significant difference in responses according to prior treatment with a CDK4/6 inhibitor or PD-L1 status. In patients with HRR alterations or microsatellite instability (MSI), the 24-week PFS rate was 67.3% (95% CI, 52.9%-79.7%), the median PFS was 9.2 months (95% CI, 7.2-16.4), the median OS was 29.5 months (95% CI, 26.6-NR), and the ORR was 37.7% (95% CI, 24.8%-52.1%). For patients with mutations solely in non-HRR and non-MSI actionable genes, the 24-week PFS rate was 51.2% (95% CI, 35.1%-67.1%), the median PFS was 7.3 months (95% CI, 5.3-10.8), the median OS was 30.0 months (95% CI, 18.7-NR), and the ORR was 23.3% (95% CI, 11.8%-38.6%).

“[Although] the results among the patients with HRR or MSI mutations are nearly similar to [that of] the global population, the results are [different] among patients with mutations solely of non-HRR or non-MSI actionable genes.”

Patients with ER-positive, HER2-negative metastatic breast cancer harboring germline BRCA1/2 pathogenic variants have known sensitivity to PARP inhibitors, and those harboring alterations in the HRR pathway may also benefit from treatment with this drug class. Genetic instability linked to mismatch repair (MMR) pathway deficiency sensitizes tumors to immune checkpoint inhibition. Within this tumor type, mutations in genes such as AKT1, ESR1, FGFR1/2/3 and PIK3CA play a role in the development of endocrine resistance.

“Moreover, luminal tumors with hypermutations may be enriched in coincident mutations in both DNA damage repair and ER-resistance signature genes, and could be sensitive to checkpoint inhibition,” Guiu added during the presentation.

Data from the phase 1/2 MEDIOLA study (NCT02734004) support this hypothesis, demonstrating synergistic activity between the PARP inhibitor olaparib and PD-L1 inhibitor durvalumab in patients with germline BRCA1/2-mutated, ER-positive, HER2-negative breast cancer. At a median follow-up of 6.7 months (IQR, 4.6-13.8) the median PFS was 8.2 months (95% CI, 4.6-11.8; 80% maturity) in this cohort.²

DOLAF was a single-arm, international study evaluating the efficacy and safety of olaparib, durvalumab and fulvestrant in patients with ER-positive, HER2-negative metastatic breast cancer with either previously documented germline BRCA1/2 mutations or somatic or germline pathogenic variants in other HRR genes; MSI status; or actionable gene mutations known to be involved in endocrine resistance.¹ An ECOG performance status (PS) of 0 or 1; 1 or more evaluable lesions as per RECIST v1.1 criteria; and exposure to prior endocrine therapy and no more than 1 line of chemotherapy was also required for study enrollment.

Guiu noted that patients with alterations in AKT1, ESR1, FGFR1/2/3, and PIK3CA were no longer eligible for inclusion onto the study following an amendment to the study protocol in May 2021. This decision was based on recent literature showing that these alterations do not confer specific sensitivity to PARP or immune checkpoint inhibitors. A subsequent amendment in April 2022 required patients to be exposed to a prior CDK4/6 inhibitor as part of prior endocrine therapy.

The trial followed an optimum Simon’s 2-stage design. The null hypothesis was a 24-week PFS rate of 50% or less, and the alternative hypothesis was a 24-week PFS rate of 65% among the first 149 evaluable patients. Because 10% percent of patients were expected to be lost to follow-up or non-evaluable, 166 patients had to be included for statistical analysis. To be considered evaluable, eligible patients must have received 1 or more doses of olaparib, durvalumab, and fulvestrant and had a tumor evaluation within approximately 28 days prior to their first treatment and at approximately 24 weeks. The safety run-in phase planned to include at least 6 and no more than 9 patients.

“Given the lack of safety data [for this combination], this study featured a safety run-in with a minimum of 6 and a maximum of 9 patients,” Guiu added.

Once enrolled, patients received 2, 300 mg doses of oral olaparib per day alongside 2, 250 mg intramuscular injections of fulvestrant on days 1 and 14 of cycle 1, and day 1 of each subsequent 28-day cycle. Starting on day 1 of cycle 2 intravenous durvalumab was administered at 1500 mg every 28 days. Goserelin was also administered to premenopausal patients.

The primary end point of the trial was 24-week PFS rate, and key secondary end points included PFS, OS, ORR, DOR, and safety. All secondary end points were also assessed in the germline BRCA1/2-mutated population.

The median age of patients enrolled onto the study was 49 years (range, 42-60) and 98.8% of patients were female. Most patients had an ECOG PS of 0 at inclusion (62%), prior receipt of a CDK4/6 inhibitor in the metastatic setting (85.5%), PD-L1 negativity (81.4%), and were included following next-generation sequencing (NGS) analysis (60.5%). Prior chemotherapy in the metastatic setting was observed in 7.6% of patients, and 39.0% displayed previously documented germline BRCA pathogenic variants. Over half of patients (64.1%) were postmenopausal, and 35.3% were premenopausal.

Regarding disease status, 96.5% of patients had distant metastases, and 3.5% had locally advanced disease. Histological types present within this population included lobular (12.9%), mixed (2.9%), and other (0.6%); 83.6% had no special type. Sites of metastasis included bone (81.3%), nodes (45.8%), liver (38.0%), lung (21.1%), pleura (9.0%), peritoneum (3.0%), central nervous system (1.8%), and other (12.7%).

From August 2019 to March 2023, 522 patients were screened by central assessment for tumor mutations across 41 centers in France, Spain, and Belgium. NGS was performed in 165 of the 172 patients initially enrolled onto the study. Four patients with germline BRCA mutations were excluded from NGS analysis due to having no tumor block or analysis not being possible, 2 were excluded for being ineligible due to a platform error, and 1 was excluded for not starting treatment.

Following NGS assessment, 62 patients were identified as having previously documented germline BRCA1/2 mutations, 53 had HRR mutations, 47 only expressed mutations in non-HRR, non-MSI actionable genes, and 1 patient was included based solely on MSI status. Among patients with HRR mutations, 2 expressed BRCA1 mutations, 8 expressed BRCA2 mutations, and 43 expressed other HRR mutations.

Results from the central NGS analysis revealed that mutations in BRCA2 (34.1%) and BRCA1 (9.8%) were the most frequently observed HRR-mutated genes, followed by PALB2 (7.9%), ATM/ATR (6.7%), and CHEK2 (4.3%). Guiu reported, “Three patients had positive MSI status but only 1 was included based on this criterion. [A total of] 36.6% of patients [expressed a] PIK3CA mutation, and 8.5% [expressed an] ESR1 mutation.”

In terms of safety, the combination was well tolerated, and no new safety signals were observed. Any-grade treatment-related adverse effects (TRAE) were observed in 93.5% of patients, 23.9% of whom experienced a grade 3 or higher AE. Serious TRAEs occurred in 16 patients (9.3%), and 2 patients (1.2%) experienced grade 5 non-TRAEs.

“Six patients completely discontinued [therapy] all due to AEs, and 34% of patients required a dose reduction of olaparib, mainly due to hematologic toxicity,” Guiu detailed, adding, “This was consistent with the well-known toxicity profile of the drug.”

The most common TRAEs occurring in more than 10% of patients were nausea (any grade, 59.6%; grade 3 or higher, 1.7%), asthenia (43.3%; 2.3%), anemia (26.3%; 9.4%), diarrhea (25.1%; 1.7%), headache (14.0%; 0.0%), hot flushes (14.0%; 0.0%), arthralgia (12.9%; 0.0%), vomiting (11.1%; 0.6%), decreased appetite (11.1%; 0.0%), fatigue (11.1%; 0.6%), and injection site pain (10.5%; 0.6%).

Immune-related AEs reported on the study included hypothyroidism (11.7%; 0.0%), hyperthyroidism (7.0%; 0.0%), drug hypersensitivity (1.2%; 0.0%), myositis (1.2%; 0.0%), renal failure (1.2%; 0.6%), rheumatic disorder (0.6%; 0.0%), hepatic failure (0.6%; 0.6%), colitis (0.6%; 0.6%), acute pancreatitis (0.6%; 0.6%), and adrenal insufficiency (0.6%; 0.6%).

“Further studies are needed to assess this combination and determine which specific subgroup could benefit most from the triplet,” Guiu concluded.

Disclosures: Dr Guiu reports having financial interests, receiving institutional funding, and serving as an invited speaker for Eli Lilly; as well as having financial Interests, receiving institutional funding, and providing expert testimony for Pfizer.

References

1. Guiu S, Balmana J, Lemercier P, et al. Combination of olaparib, durvalumab and fulvestrant in patients with advanced ER-positive, HER2-negative breast cancer harboring homologous recombination repair (HRR) deficiency or microsatellite instability (MSI): results of the international phase II DOLAF trial. Presented at: 2024 ESMO Breast Cancer Annual Congress; May 15-17, 2024; Berlin, Germany. Abstract 179O.
2. Domchek SM, Postel-Vinay S, Im SA, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 2020;21(9):1155-1164. doi:10.1016/S1470-2045(20)30324-7