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Adjuvant Olaparib for High-Risk, Early Breast Cancer in BRCA1/2 Pathogenic or Likely Pathogenic Variant Carriers: Implications for Clinical Practice

Oncology
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Acknowledgments: Stefania Morganti, MD, and Filipa Lynce, MD, for their leadership in the consensus discussions and in writing of the statements. Coordination and editorial support were performed by Mr. Scorzoni and Ms. Bak.

Synopsis

  1. Consensus statements for the use of adjuvant olaparib in gBRCA carriers with early- stage triple negative breast cancer (TNBC)
Clinical QuestionConsensus Statement
Q1. What should be the initial recommended treatment strategy to gBRCAm patients who received neoadjuvant chemo-immunotherapy and had residual disease at surgery?1-year adjuvant olaparib is recommended for gBRCAm patients who received neoadjuvant chemo-immunotherapy and had residual disease at surgery. Additional pembrolizumab may be considered.
Q2. Should olaparib and pembrolizumab be given concomitantly?When both olaparib and pembrolizumab are considered, concurrent administration should be preferred, if adequately tolerated.
Q3. Should both capecitabine and olaparib be offered and given sequentially?Olaparib should be preferred over capecitabine  in  patients with residual disease after neoadjuvant therapy. Sequential administration of olaparib and capecitabine may be offered to patients at “very high” risk of recurrence.
Q4. Should olaparib be considered in TNBC patients with poor response to platinum?Olaparib should be considered in TNBC patients with suboptimal response to platinum (i.e., residual disease despite neoadjuvant platinum).
Q5. Which patients with TNBC should receive adjuvant olaparib after adjuvant chemotherapy?Adjuvant olaparib after adjuvant chemotherapy should be recommended for stage II-III TNBC, according to the OlympiA criteria. Adjuvant olaparib should not be recommended for patients with stage I TNBC.
  1. Consensus statements for the use of adjuvant olaparib in gBRCA carriers with early-stage, hormone receptor (HR)-positive/HER2-negative (HR+/HER2-) breast cancer
Clinical QuestionConsensus Statement
Q6: What treatment should be recommended after adjuvant chemotherapy to gBRCAm patients with HR+/HER2- breast cancer and ≥4 positive axillary lymph nodes?Adjuvant olaparib should be preferred over abemaciclib after adjuvant chemotherapy in gBRCAm patients with early-stage, HR+/HER2- breast cancer and ≥4 positive axillary lymph nodes. Sequential administration of olaparib and abemaciclib may be considered in very high-risk patients.
Q7: What treatment should be recommended after adjuvant chemotherapy to gBRCAm patients with HR+/HER2- breast cancer and 1-3 positive axillary lymph nodes?Adjuvant olaparib should be considered after adjuvant chemotherapy in gBRCAm patients with early-stage, HR+/HER2- breast cancer and 1-3 positive axillary lymph nodes. Abemaciclib may be considered as an alternative.
Q8. What treatment should be recommended after adjuvant chemotherapy to gBRCAm patients with high-risk, node-negative HR+/HER2- breast cancer?Adjuvant olaparib should not be recommended to early-stage, node-negative, HR+/HER2- breast cancer after adjuvant chemotherapy.
Q9: What treatment should be recommended after neoadjuvant chemotherapy to gBRCAm patients with early-stage, HR+/HER2- breast cancer and ≥4 positive axillary lymph nodes at surgery?Adjuvant olaparib should be recommended after neoadjuvant chemotherapy in gBRCAm patients with early-stage, HR+/HER2- breast cancer and ≥4 positive axillary lymph nodes. Sequential administration of olaparib and abemaciclib may be considered in high-risk patients.
Q10: What treatment should be recommended after neoadjuvant chemotherapy to gBRCAm patients with early-stage, HR+/HER2- breast cancer and 1-3 axillary lymph nodes at surgery?Adjuvant olaparib should be considered after neoadjuvant chemotherapy in gBRCAm patients with early-stage, HR+/HER2- breast cancer and 1-3 positive axillary lymph nodes. Abemaciclib should be considered as an alternative. Sequential administration of adjuvant olaparib followed by abemaciclib may be considered in high-risk patients.
Q11: What treatment should be recommended to patients with high-risk, node-positive HR+/HER2- breast cancer who do not receive chemotherapy?Adjuvant olaparib should be considered for patients with high- risk, node-positive, HR+/HER2- disease who do not receive chemotherapy. Sequential administration  of  olaparib followed by abemaciclib may be considered for high-risk patients.
Q12: Should olaparib be administered concurrently with endocrine therapy?Adjuvant olaparib and endocrine therapy should be administered concurrently.
Q13: If both abemaciclib and olaparib are considered, which agent should be offered first?Administration of olaparib followed by abemaciclib should be preferred when sequential administration of both agents is considered.
Q14: What should be the preferred strategy for gBRCAm patients currently on abemaciclib?Treatment switching to olaparib should be considered for patients currently receiving abemaciclib. Timing of switching should be defined on a case-by-case basis.
  1. Consensus statements for the use of adjuvant olaparib in gBRCA carriers with early-stage ER-low breast cancer
Clinical QuestionConsensus Statement
Q15. Should olaparib be offered to gBRCA carriers with ER-low breast cancer according to the OlympiA inclusion criteria defined for TNBC or HR-positive population?Olaparib should be offered to gBRCA carriers with ER-low breast cancer according to the OlympiA inclusion criteria defined for TNBC (i.e., non-pCR after neoadjuvant chemotherapy; ≥pT2 and/or node-positive disease after surgery and adjuvant chemotherapy).
Q16. Should adjuvant olaparib be administered with endocrine therapy in patients with ER-low breast cancer?When adjuvant endocrine therapy is considered, adjuvant olaparib may be administered concurrently in gBRCAm carriers with ER-low breast cancer.
Q17. If neoadjuvant pembrolizumab was administered to gBRCA carriers with ER- low breast cancer and residual disease at surgery, should pembrolizumab, endocrine therapy and olaparib be administered concurrently as post- neoadjuvant therapy?Concurrent administration of adjuvant pembrolizumab, endocrine therapy and olaparib may be considered. Sequential administration of adjuvant olaparib followed by abemaciclib may be considered in high-risk patients.
  1. Consensus statements for the use of adjuvant olaparib in gPALB2 carriers with early-stage HER2- breast cancer
Clinical QuestionConsensus Statement
Q18. Should adjuvant olaparib be considered in gPALB2m patients with HER2-negative early breast cancer according to the OlympiA criteria?Adjuvant olaparib may be considered in gPALB2m patients with HER2-negative early breast cancer according to the OlympiA criteria.
  1. Consensus statements for the use of adjuvant olaparib and the impact on fertility
Clinical QuestionConsensus Statement
Q19. Should adjuvant olaparib be considered independently of future pregnancy plans?Decisions regarding fertility preservation and timing of subsequent pregnancy should be based on what is known about fertility after standard cytotoxic therapy, patient age and preferences, recognizing the uncertainty in this field.
  1. Consensus statements on germline genetic testing in patients with early breast cancer
Clinical QuestionConsensus Statement
Q20. Which patients should be tested for gBRCA status?Germline genetic testing should be  offered to patients according to the NCCN criteria, including patients who might be eligible for adjuvant olaparib. Additionally, testing may be considered in patients aged 45-65 otherwise not included in the NCCN criteria.
  1. Consensus statements on toxicity monitoring and management in gBRCAm carriers with early breast cancer receiving adjuvant olaparib
Clinical QuestionConsensus Statement
Q21. What monitoring should be used for patients receiving adjuvant olaparib?Patients receiving adjuvant olaparib should be monitored according to the OlympiA protocol, i.e., complete blood count (CBC) and comprehensive metabolic panel (CMP) bi-weekly for 1 month, then monthly for five months. CBC monitoring after the first 6 months of treatment should be personalized based on tolerance.

Background

Evidence in support of use of adjuvant olaparib for germline BRCA1/2 carriers with early breast cancer
On March 16, 2022, the OlympiA phase III, double-blind, randomized trial reported the overall survival efficacy of adjuvant olaparib in patients with early-stage, human epidermal growth factor receptor 2 (HER2)–negative breast cancer with high risk of recurrence and germline BRCA1 or BRCA2 pathogenic or likely pathogenic (P/LP) variants.[1]
The OlympiA trial randomized 1836 patients to receive 1 year of adjuvant olaparib or placebo.[1,2] All eligible patients had a germline BRCA1 or BRCA2 P/LP variants and received neoadjuvant or adjuvant chemotherapy. Patients with triple-negative breast cancer (TNBC) treated with adjuvant chemotherapy were required to have node–positive disease or an invasive primary tumor of at least 2 cm, whereas patients receiving neoadjuvant chemotherapy were required to have residual disease at surgery.
Patients with hormone receptor (HR)–positive breast cancer receiving adjuvant chemotherapy were required to have at least four pathologically confirmed positive lymph nodes, whereas those receiving neoadjuvant chemotherapy were required to have residual disease and a CPS+EG score of 3 or higher.
The primary endpoint was invasive disease-free survival (iDFS), secondary endpoints were distant disease-free survival (DDFS), overall survival (OS) and safety.
On June 2021, at the first pre-planned interim analysis after a median follow up of 2.5 years, there was significant iDFS improvement, with a 3-year IDFS of 85.9% in the olaparib group and 77.1% in the placebo group (hazard ratio [HR] for invasive disease or death 0.58; 99.5% CI 0.41 to 0.82; p<0.001)[2].
On March 2022, at the second planned interim analysis after a median follow up of 3.5 years, a significant OS benefit was reported (3-year OS 92.8% with olaparib versus 89.1% with placebo; stratified HR 0.68; 98.5% CI 0.47 to 0.97; p=0.009)[1].
Presently, 1-year adjuvant olaparib is recommended by ASCO[3] and NCCN[4] guidelines for gBRCA carriers with high-risk, early-stage, HER2-negative breast cancer according to the inclusion criteria of the OlympiA study.
On March 11, 2022, the US Food and Drug Administration (FDA) approved olaparib for the adjuvant treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy[5].
Development of the Consensus Statements
Dana-Farber Cancer Institute’s Breast Oncology Center (BOC) held multidisciplinary meetings on May 6, May 20, and June 1, 2022 to discuss recommendations for the use of olaparib in patients with P/LP gBRCA1 or gBRCA2 mutations (gBRCAm) and high-risk early breast cancer. Gathered evidence on the use of adjuvant olaparib was presented for discussion to a multidisciplinary group, which included physicians, nurses, clinical investigators, lab investigators, translational researchers, administrators, and patient advocates at the BOC weekly staff meetings.
The discussion and suggestions for improvements continued via email exchanges following the meeting. The final consensus statements were consolidated in July and August of 2022.
The consensus statements can be subject to future variations and periodic updates, based on emerging evidence and new reports from ongoing clinical studies. Therefore, the information provided in this document should not be considered as being complete or inclusive of all proper assessments, treatments or methods of care or as a statement of the standard of care. This information does not mandate any particular course of medical care and is not intended to be a substitute for the independent professional judgment of a health care provider.
The document is based on the opinion of a multidisciplinary team at Dana-Farber but does not represent the official institutional position, and overall must be considered as a consensus based on the positions and ideas of Dana-Farber providers.

Clinical Questions

Adjuvant olaparib for gBRCA carriers with early-stage triple negative breast cancer

Q1. What should be the initial recommended treatment strategy for gBRCAm patients who received neoadjuvant chemo-immunotherapy and had residual disease at surgery?
Evidence in support: Neoadjuvant pembrolizumab plus anthracycline, taxane, and carboplatin-based chemotherapy, followed by adjuvant pembrolizumab, is recommended for patients with high-risk, stage II-III TNBC based on the event-free survival (EFS) benefit showed in the KEYNOTE-522 (KN522) study [6,7].
In this study, gBRCA status was reported only for 17.9% of patients, with 54 known gBRCA carriers enrolled (40 in the experimental arm and 14 in the placebo arm). gBRCA status was missing/undetermined in 82.1% of patients[8]. In the IMpassion130 study, which randomized patients with metastatic TNBC to receive first-line nab-paclitaxel with or without atezolizumab, the benefit of the addition of immunotherapy was observed regardless of gBRCA status[9].
Administration of pembrolizumab was not allowed in the OlympiA study, as it was not standard of care when the study was designed. Analogously, adjuvant olaparib was not allowed in the KN522 study.
The lack of pathologic complete response (pCR) after neoadjuvant chemo-immunotherapy for TNBC is associated with high risk of relapse[10]. Despite the lack of data in this setting, the consensus within the BOC group was to recommend adjuvant olaparib after neoadjuvant chemo-immunotherapy in patients with residual disease considering the strong OS benefit shown by the OlympiA study.
Consensus Statement 1.
1-year adjuvant olaparib is recommended for gBRCAm patients who received neoadjuvant chemo-immunotherapy and had residual disease at surgery. Concurrent adjuvant pembrolizumab may be considered.
Q2. Should olaparib and pembrolizumab be given concomitantly?
Evidence in support: There are currently no safety and efficacy data available regarding concurrent administration of PARP inhibitors (PARPi) and immunotherapy in patients with early-stage breast cancer. A number of trials investigated their co-administration in the metastatic setting showed good tolerability (i.e., TOPACIO[11], MEDIOLA[12], KEYLYNK-007[13] trials), although none of the trials compared efficacy of PARPi monotherapy versus PARPi plus immunotherapy. The ETCTN 10020 trial, investigating olaparib with or without atezolizumab in gBRCAm patients with advanced breast cancer, has completed enrolment and results are awaited (NCT02849496).
When considering administration of both olaparib and pembrolizumab, the BOC group favored concurrent administration of both agents, if adequately tolerated.
Consensus Statement 2. When both olaparib and pembrolizumab are considered, concurrent administration should be preferred, if adequately tolerated.
Q3. Should both capecitabine and olaparib be offered and given sequentially?
Evidence in support: In the phase III CREATE-X study [14], 6-8 cycles of adjuvant capecitabine were shown to increase both iDFS and OS in patients with TNBC and residual disease after neoadjuvant chemotherapy. Prior to the approval of adjuvant olaparib, post-neoadjuvant capecitabine was standard practice in both gBRCAm and gBRCA wild-type (wt) patients. Administration of capecitabine was not allowed in the OlympiA and KN522 studies.
There is no head-to-head data comparing adjuvant capecitabine and olaparib in this setting. Correlative data from the GEICAM[15] study suggested that the benefit of capecitabine is mainly obtained by patients with non-basal-like subtypes and is lower in patients with basal-like tumors, as most gBRCA-associated TNBC. Similarly, in the EA1131 study, patients with non-basal subtypes seemed to derive a higher benefit from capecitabine than platinum-based chemotherapy, although the finding was not significant[16].
In the EMBRACA[17] and OlympiAD[18,19] studies, a progression-free survival (PFS) benefit of PARPi over physician’s choice of chemotherapy was observed for gBRCAm patients with advanced breast cancer. Capecitabine was the most frequently administered chemotherapy in both trials.
The BOC group favored administration of olaparib over capecitabine in TNBC patients with residual disease after neoadjuvant chemotherapy. Sequential administration of the two agents was endorsed only for patients considered at “very high” risk. The BOC group recommended against concurrent administration given the overlapping toxicity profile of capecitabine and olaparib.
Consensus Statement 3.
Olaparib should be preferred over capecitabine in patients with residual disease after neoadjuvant therapy. Sequential administration of olaparib and capecitabine may be offered to patients at “very high” risk of recurrence.
Q4: Should olaparib be considered in TNBC patients with poor response to platinum?
Evidence in support. Data regarding the efficacy of PARPi in gBRCAm patients with poor response to platinum are limited. The OlympiAD[19] and EMBRACA[20] trials did not allow enrollment of platinum-refractory patients although patients with prior exposure and no progression on platinum were allowed to participate. The BrighTNess study[21] investigated the addition of carboplatin to neoadjuvant chemotherapy in patients with early-stage TNBC and there was no significant difference in pCR among treatment arms by BRCA status.
In the OlympiA study, all patients treated with neoadjuvant chemotherapy had residual disease per inclusion criteria, including those receiving platinum (~26%)[2]. Although the absence of pCR might be interpreted as suboptimal response to platinum, the subgroup analysis showed that the benefit of olaparib was maintained also in platinum pre-treated patients.
The BOC group endorsed the lack of data to discourage administration of olaparib in patients with suboptimal response to platinum.
Consensus Statement 4.
Olaparib should be considered in TNBC patients with suboptimal response to platinum (i.e., residual disease despite neoadjuvant platinum).
Q5: Which patients with TNBC should receive adjuvant olaparib after adjuvant chemotherapy?
Evidence in support. In the OlympiA study, patients with TNBC enrolled after adjuvant chemotherapy were required to have invasive disease at surgery of at least 2 cm or axillary lymph node involvement. The FDA approved adjuvant olaparib for high-risk patients after (neo)adjuvant chemotherapy, thus extending eligibility to patients with stage I TNBC treated with adjuvant chemotherapy.
Most stage I TNBC patients have very good outcomes[22]. The use of adjuvant olaparib after chemotherapy may thus represent an overtreatment for many of these patients.
The BOC group recognized the lack of data so far supporting the use of adjuvant olaparib in stage I TNBC. Whether olaparib might instead replace chemotherapy in this subgroup of patients warrants further investigation.
Oppositely, the BOC group recognized that some high-risk patients with TNBC might not receive chemotherapy, such as in the case of comorbidities that contra-indicate chemotherapy or due to patient’s refusal. Considering their high risk or recurrence, olaparib should be considered for TNBC patients who do not receive chemotherapy but otherwise meet OlympiA criteria.
Consensus Statement 5.
Adjuvant olaparib after adjuvant chemotherapy should be recommended for stage II-III TNBC, according to the OlympiA criteria. Adjuvant olaparib should not be recommended for patients with stage I TNBC.
Adjuvant olaparib for gBRCA carriers with early-stage hormone receptor (HR)-positive/HER2-negative (HR+/HER2-) breast cancer
Evidence in support: Based on the iDFS benefit showed in the monarchE trial[23], 2-year adjuvant abemaciclib is recommended for high-risk, HR+ early breast cancer regardless of gBRCA status. Adjuvant olaparib was not allowed in the monarchE study, as it was not standard practice when the study was designed.
There is no data comparing head-to-head adjuvant abemaciclib and olaparib in high-risk, HR+/HER2- early-stage breast cancer. Although both are currently approved in this setting, inclusion criteria of the monarchE and OlympiA trials differed and overlapped only partially. Prior treatment with chemotherapy was not required by the monarchE study, though 95% of enrolled patients received chemotherapy[23].
To be eligible for the monarchE study, patients were required to have more than 4 axillary lymph nodes involved at surgery, or 1-3 positive lymph nodes and either grade 3 or tumor size larger than 5 cm or a Ki67 20%. There was no distinction between patients receiving neoadjuvant or adjuvant chemotherapy.
In the OlympiA study2, patients with HR+ tumors receiving adjuvant chemotherapy were eligible only if they had more than 4 positive axillary lymph nodes. Patients treated with neoadjuvant chemotherapy were eligible if there was residual disease at surgery and a CPS-EG score equal or higher than 3.
The CPS+EG is a prognostic score estimating the risk of recurrence after neoadjuvant chemotherapy[24]. It’s based on clinical stage, pathologic stage, estrogen receptor status and nuclear grade on pretreatment tumor biopsy.
Although all patients with CPS+EG≥3 have high-risk tumors, the opposite is not confirmed, and some high-risk tumors have CPS+EG score lower than 3. For instance, clinical stage III, grade II ER+ tumors with pathological stage III after neoadjuvant chemotherapy have a CPS-EG score of 2.
Q6: What treatment should be recommended after adjuvant chemotherapy to gBRCAm patients with HR+/HER2- breast cancer and ≥4 positive axillary lymph nodes?
Q7: What treatment should be recommended after adjuvant chemotherapy to gBRCAm patients with HR+/HER2- breast cancer and 1-3 positive axillary lymph nodes?
Q8. What treatment should be recommended after adjuvant chemotherapy to gBRCAm patients with high-risk, node-negative HR+/HER2- breast cancer?
Evidence in support: Patients with more than 3 positive lymph nodes at surgery receiving adjuvant chemotherapy were included in both the OlympiA[2] and monarchE trial[23], whereas patients with 1-3 positive lymph nodes were excluded from OlympiA and their inclusion in monarchE was dependent on tumor grade, Ki67 or tumor size. Patients with node-negative disease were not included in the OlympiA nor in the monarchE trials.
The FDA label of adjuvant olaparib allows its administration to all patients considered at “high-risk” of recurrence after neoadjuvant chemotherapy, independently of the number of nodes involved[5]. gBRCA carriers are more likely to have HR+ breast cancer with high Oncotype Dx recurrence score, thus they are candidates to receive adjuvant chemotherapy independently of nodal status.
The OS benefit observed in the OlympiA study was maintained in the HR+ positive population. Preliminary OS data from the monarchE trial did not show a survival benefit (HR 0.767, CI 0.511-1.152), although data were still immature (median follow up 27.1 months) and the OS analysis was not preplanned [25]. 
The BOC group favored olaparib over abemaciclib in patients with HR+ breast cancer and 4 or more positive lymph nodes. For patients with 1-3 positive nodes, the BOC group recognized the lack of data supporting adjuvant olaparib, although it was discussed that these patients might derive a benefit from olaparib. The group also underlined the lack of OS benefit observed in the monarchE study, the short follow up, and the lack of data about benefit of abemaciclib among gBRCA carriers.
The BOC group agreed on the use of both drugs in sequence for high-risk patients.
Due to the lack of data in node-negative patients, the BOC group recommended against administration of adjuvant olaparib in this subgroup of patients.
Consensus Statement 6.
Adjuvant olaparib should be preferred over abemaciclib after adjuvant chemotherapy in gBRCAm patients with early-stage, HR+/HER2- breast cancer and ≥4 positive axillary lymph nodes. Sequential administration of olaparib and abemaciclib may be considered in very high-risk patients.
Consensus Statement 7.
Adjuvant olaparib should be considered after adjuvant chemotherapy in gBRCAm patients with early-stage, HR+/HER2- breast cancer and 1-3 positive axillary lymph nodes. Abemaciclib may be considered as an alternative.
Consensus Statement 8.
Adjuvant olaparib should not be recommended to patients with early-stage, node-negative, HR+/HER2- breast cancer after adjuvant chemotherapy.
Q9: What treatment should be recommended after neoadjuvant chemotherapy to gBRCAm patients with early-stage, HR+/HER2 breast cancer and ≥4 positive axillary lymph nodes at surgery?
Q10: What treatment should be recommended after neoadjuvant chemotherapy to gBRCAm patients with early-stage, HR+ breast cancer and 1-3 positive axillary lymph nodes at surgery?
Evidence in support: In the monarchE trial, inclusion criteria were equal for patients receiving neoadjuvant or adjuvant chemotherapy. Indeed, patients with early-stage HR+ breast cancer were eligible for study inclusion if they had more than 4 positive axillary lymph nodes or 1-3 positive nodes and additional risk factors.
In the OlympiA study, enrollment for patients receiving neoadjuvant chemotherapy was dependent on the CPS+EG score, although the FDA label allows treatment with adjuvant olaparib for all patients considered at high risk of recurrence, without specific consideration of the CPS+EG score.
Considering the OS benefit observed with adjuvant olaparib and the limitations of the CPS+EG score in identifying all high-risk patients, the consensus of the BOC group favored adjuvant olaparib over abemaciclib. Sequential administration of both agents was endorsed for high-risk patients.
Consensus Statement 9.
Adjuvant olaparib should be recommended after neoadjuvant chemotherapy in gBRCAm patients with early-stage, HR+/HER2- breast cancer and ≥4 positive axillary lymph nodes at surgery. Sequential administration of olaparib and abemaciclib may be considered in high-risk patients.
Consensus Statement 10.
Adjuvant olaparib should be considered after neoadjuvant chemotherapy in gBRCAm patients with early-stage, HR+/HER2- breast cancer and 1-3 positive axillary lymph nodes. Abemaciclib should be considered as an alternative. Sequential administration of adjuvant olaparib followed by abemaciclib may be considered in high-risk patients.
Q11. What treatment should be recommended to gBRCAm patients with high-risk, node-positive disease who do not receive chemotherapy?
Evidence in support: According to results of the RxPONDER trial[26], there is no added benefit of adjuvant chemotherapy over endocrine therapy alone in postmenopausal patients with low or intermediate OncotypeDx recurrence score, although an age-modifying effect was seen in premenopausal women. Accordingly, not all patients with node-positive early-stage HR+ breast cancer are candidates to receive adjuvant chemotherapy. However, most of them are still at moderate to high risk of recurrence.
Patients not receiving chemotherapy were not enrolled in the OlympiA study and represented 5% of the population included in the monarchE study. Despite the lack of representation of these patients in OlympiA, and the perception that the benefit of olaparib likely expands beyond the high-risk patients included in OlympiA, the BOC group favored administration of olaparib and both agents in sequence for very-high-risk patients who did not receive chemotherapy.
Consensus Statement 11.
Adjuvant olaparib should be considered for patients with high-risk, node-positive disease who do not receive chemotherapy. Sequential administration of olaparib followed by abemaciclib may be considered in high-risk patients.
Q12. Should olaparib be administered concurrently with endocrine therapy?
Evidence in support: There is no data comparing efficacy of olaparib plus endocrine therapy versus olaparib alone.
A preliminary analysis of the D081CC00001 study[27], combining olaparib with endocrine therapy, did not show clinically relevant drug-drug interaction between olaparib and tamoxifen, letrozole, or anastrozole. Based on these findings, gBRCAm patients with HR+ breast cancer in the OlympiA trial were allowed to receive endocrine therapy at any time during the study and 87% of patients did receive concurrent administration. According to the OlympiA subgroup analysis, benefit of adjuvant olaparib was maintained for both HR+ and TNBC patients and there was no concern for decreased clinical benefit with the addition of ET[2].
Based on the OlympiA findings, the consensus from the group favored concurrent administration of olaparib and endocrine therapy.
Consensus Statement 12.
Adjuvant olaparib and endocrine therapy should be administered concurrently.
Q13: If both abemaciclib and olaparib are considered, which agent should be offered first?
Evidence in support: There are no safety data available for the combination of abemaciclib and olaparib, which share partially overlapping toxicity profiles. The HOPE trial, testing the combination of CDK4/6 inhibitor (palbociclib), PARPi (olaparib) and endocrine therapy (fulvestrant) in the metastatic setting, is ongoing (NCT0368533). Therefore, when considering both abemaciclib and olaparib, these should not be given concomitantly.
In the MonarchE trial, abemaciclib was allowed to be started up to 16 months after surgery[23]. In the OlympiA study, olaparib was allowed to be started up to 8 weeks after completion of primary therapy[2].
There is no head-to-head comparison between CDK4/6i and PARPi plus endocrine therapy. However, a correlative study from the Memorial Sloan Kettering Cancer Center suggests a reduced benefit from CDK4/6i in gBRCA2 carriers with metastatic breast cancer[28].
Considering these data and OS benefit from olaparib, the BOC group recommended administration of olaparib first when both agents are considered.
Consensus Statement 13.
Administration of olaparib followed by abemaciclib should be preferred when sequential administration of both agents is considered.
Q14: What should be the preferred strategy for gBRCAm patients currently on abemaciclib?
Evidence in support: Considering the approval of adjuvant olaparib after adjuvant abemaciclib, it is likely that a proportion of patients who were candidates for adjuvant olaparib started abemaciclib instead. There is no data suggesting what should be the preferred strategy for these patients.
Acknowledging the lack of data, the BOC group favored a case-by-case decision regarding a switching strategy.
Consensus Statement 14.
Treatment switching to olaparib should be considered for patients currently receiving abemaciclib. Timing of switching should be defined on a case-by-case basis.

Adjuvant olaparib for gBRCA carriers with early-stage ER-low breast cancer

Q15. Should olaparib be offered to gBRCA carriers with ER-low breast cancer according to the OlympiA inclusion criteria defined for TNBC or HR-positive population?
Q16. Should adjuvant olaparib be administered with endocrine therapy in patients with ER-low breast cancer?
Q17. If neoadjuvant pembrolizumab was administered to gBRCA carriers with ER-low breast cancer and residual disease at surgery, should pembrolizumab, endocrine therapy, and olaparib be administered concurrently as post-neoadjuvant therapy?
Evidence in support: In 2020, the ASCO/CAP guidelines on estrogen and progesterone receptor testing in breast cancer defined tumors with estrogen receptor (ER) expression between 1 and 10% as a new reporting category: ER low positive[29]. This statement was based on the limited data about endocrine therapy benefit for cancers with low expression of ER.
ER-low breast tumors have pathologic features intermediate between ER>10% and ER-negative tumors. When compared to ER>10%, ER-low tumors are more frequently basal-like and high-grade[30-33]. Most of ER-positive tumors occurring in gBRCA carriers are ER-low, especially among BRCA1 carriers[30].
Retrospective studies showed a similar risk of recurrence and death for ER-low and TNBC, although the outcome of the ER-low breast cancer patients receiving endocrine therapy was better compared to patients not treated with endocrine therapy[34].
In the OlympiA study, gBRCA carriers with ER-low breast cancer were included in the HR-positive population and were eligible for inclusion according to those criteria[2]. Most patients received concurrent endocrine therapy. However, no subgroup analysis of treatment patterns and outcomes according to ER level of expression has been published.
According to BOC internal guidelines, neoadjuvant pembrolizumab plus chemotherapy (KN522 regimen) followed by adjuvant pembrolizumab may be considered for patients with ER-low breast cancer.
Considering available data about the biology, treatment patterns, and outcomes of ER-low breast cancers, the BOC group agreed that adjuvant olaparib recommendations for this group of patients should follow the OlympiA inclusion criteria for TNBC. Our group agreed on recommending adjuvant olaparib in gBRCA carriers with ER-low breast cancer receiving the KN522 neoadjuvant regimen with residual disease at surgery. Coadministration of adjuvant pembrolizumab and endocrine therapy may be considered.
Consensus Statement 15.
Olaparib should be offered to gBRCA carriers with ER-low breast cancer according to the OlympiA inclusion criteria defined for TNBC (i.e., non-pCR after neoadjuvant chemotherapy; ≥pT2 and/or node-positive disease after surgery and adjuvant chemotherapy).
Consensus Statement 16.
When adjuvant endocrine therapy is considered, adjuvant olaparib may be administered concurrently in gBRCAm carriers with ER-low breast cancer.
Consensus Statement 17.
Concurrent administration of adjuvant pembrolizumab, endocrine therapy and olaparib may be considered. Sequential administration of adjuvant olaparib followed by abemaciclib may be considered in high-risk patients.

Adjuvant olaparib for germline PALB2 carriers with early-stage HER2-breast cancer

Q18. Should adjuvant olaparib be considered in gPALB2m patients with HER2-negative early breast cancer according to the OlympiA criteria?
Evidence in support: Germline PALB2 (gPALB2) carriers with early-stage, HER2- breast cancer were not included in the OlympiA trial[2].
TBCRC 048 was a phase 2 trial investigating olaparib in metastatic breast cancer patients carrying either a germline mutation in an homologous recombination-related gene other than BRCA1/2 or a somatic mutation in an HR-related gene[35]. Among patients with a gPALB2 mutation, 82% had a response and all had clinical benefit[35].
Despite the lack of data in patients with early-stage breast cancer, the BOC group recognized that data available in the metastatic setting do suggest that gPALB2 carriers with early breast cancer are likely to derive benefit from adjuvant olaparib.
Consensus Statement 18.
Adjuvant Olaparib may be considered in gPALB2m patients with HER2-negative early breast cancer according to the OlympiA criteria.

Adjuvant olaparib and fertility

Q19. Should adjuvant olaparib be considered independently of future pregnancy plans?
Evidence in support: Preclinical data suggest that gBRCA mutation carriers may have a reduced ovarian reserve (BRCA1 in particular). Nevertheless, clinical data have not identified a difference in terms of fertility between gBRCA-carriers and non-carriers[36,37].
There is no clinical data available regarding the impact of adjuvant olaparib on fertility. A preclinical study evaluating gonadotoxicity of olaparib on female rats did not detect adverse effects on mating and fertility rates. In this study, olaparib was administered for at least 14 days before mating through the first week of pregnancy[5].
In this context, there is uncertainty about the potential impact of PARPi on future fertility of breast cancer survivors. Decisions surrounding fertility preservation and timing of subsequent pregnancy should therefore be based on what is known about fertility after standard cytotoxic therapy as well as patient age and preferences, and in light of the risks of the patient’s breast cancer.
Consensus Statement 19.
Decisions regarding fertility preservation and timing of subsequent pregnancy should be based on what is known about fertility after standard cytotoxic therapy, patient age and preferences, recognizing the uncertainty in this field.

Criteria for germline genetic testing in patients with early breast cancer

Q20. Which patients should be tested for gBRCA status?
Evidence in support: Most guidelines recommend germline testing for high-penetrance genes associated with breast cancer according to the pre-test probability of carrying a germline alteration, thus on the basis of tumor subtype, age, patient and family history[38].
A number of retrospective analyses outlined the limitation of these criteria . For instance, NCCN criteria were shown to fail to detect 9% of pathogenic variants in BRCA1/2 given a 60 year cut-off for testing and 12% given a 65 year cut-off[39,40].
On the other hand, prevalence of gBRCA variants among patients not meeting NCCN guidelines was low (1.9% <60; 1.7% <65) and the incremental yield if all patients were tested for BRCA1/2/PALB2 was only 0.36%-0.42%[39,40].
More recently, NCCN recommendations for testing have been extended to aid in adjuvant treatment decisions related to olaparib.
Despite the low prevalence of gBRCA variants in older patients, the BOC group acknowledged that the survival benefit observed in the OlympiA trial justifies extending testing to all patients meeting the OlympiA criteria. Considering the additional benefit in terms of surgical management, screening for secondary tumors and family involvement, the group agreed that testing may be considered for all patients with HER2- early breast cancer.
Consensus Statement 20.
Germline genetic testing should be offered to patients according to the NCCN criteria, including patients who might be eligible for adjuvant olaparib. Additionally, testing may be considered in patients aged 45-65 otherwise not included in the NCCN criteria.

Adjuvant olaparib: toxicity monitoring and management

Q21. What monitoring should be used for patients receiving adjuvant olaparib?
Evidence in support: In the OlympiA trial, the safety profile of adjuvant olaparib was consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. Most frequent side effects were nausea (57%), fatigue (40%), anemia (23.5%), vomiting (22.6%), headache (19.8%). Hematological toxicities represented the most common high grade (grade≥3) adverse events: anemia (8.7%), decreased neutrophil count (4.8%), decreased white-cell count (3.0%) [1,2].
In the metastatic setting, administration of PARP inhibitors has been associated with an increased risk of developing myelodysplastic syndromes (MDS) and/or acute myeloid leukemia (AML). After a median follow up of 3.5 years, the incidence of MDS/AML was similar between the two arms (2 events in the olaparib arm and 3 in the placebo arm).
In the OlympiA trial, complete blood count (CBC) and comprehensive metabolic panel (CMP) were checked every 2 weeks during the first month, then monthly up to six months of treatment, then every 6 months in the last 6 months.
The FDA label recommends CBC monitoring at baseline and monthly thereafter.
In case of myelotoxicity, olaparib was interrupted, reduced or permanently discontinued according to Table 1.
Management of hematological toxicity
CTCAE grade 1-2• Continue olaparib or withheld per investigator’s judgement
Repeat CTCAE grade 1-2• Withheld olaparib until recovery to grade 1;
• Reduce olaparib dose to 250 mg BID
• If a further dose reduction is required, reduce to 200 mg BID
CTCAE grade 3-4• Withheld olaparib until recovery to grade 1;
• Reduce olaparib dose to 200 mg BID
Repeat CTCAE grade 3-4• Permanently discontinue olaparib
In case of prolonged hematological toxicity (see below), patients were monitored with weekly CBC, including reticulocytes and peripheral blood smear:
  • ≥2-week interruption/delay in study treatment due to CTC grade ≥3 anemia and/or development of blood transfusion dependence
  • ≥2-week interruption/delay in study treatment due to CTC grade ≥3 neutropenia (ANC < 1 x 109/L)
  • ≥2-week interruption/delay in study treatment due to CTC grade ≥3 thrombocytopenia (Platelets < 50 x 109/L). In case of toxicity lasting more than 4 weeks after dose interruption (6 weeks for hemoglobin recovery), the patient did discontinue permanently study treatment and were referred to hematologist for further investigations.
The BOC group agreed on monitoring CBC according to the OlympiA trial, thus with CBC every two weeks in the first month and monthly thereafter for the first 6 months. Monitoring in the following 6 months should be based on individual tolerance.
Consensus Statement 21.
Patients receiving adjuvant olaparib should be monitored according to the OlympiA protocol, i.e., complete blood count (CBC) and comprehensive metabolic panel (CMP) bi-weekly for 1 month, then monthly for five months. CBC monitoring after the first 6 months of treatment should be personalized based on tolerance.

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