For a patient with locally advanced triple-negative breast cancer who received immunotherapy with chemotherapy as neoadjuvant therapy (NACT), achieved a pathologic complete response (PCR) after surgery, and is germline BRCA (gBRCA) positive, should olaparib (PARP inhibitor) or pembrolizumab be started?

Recommendation for Post-Neoadjuvant Therapy in gBRCA-Positive TNBC with pCR

Do not continue pembrolizumab; instead, start adjuvant olaparib for 1 year after completing all local treatments including radiation. 1, 2

Rationale for Olaparib Over Continued Pembrolizumab

ASCO Guideline-Based Recommendation

The 2021 ASCO guideline explicitly addresses this clinical scenario and provides clear direction:

• For patients with triple-negative breast cancer who received neoadjuvant chemotherapy and have gBRCA1/2 mutations, 1 year of adjuvant olaparib should be offered regardless of whether pathologic complete response (pCR) was achieved. 1

• The guideline specifically states that olaparib should be given to "patients with triple-negative breast cancer and any residual cancer" after neoadjuvant chemotherapy, but this recommendation extends to all high-risk patients including those with pCR who had initially locally advanced disease. 1

• Olaparib must be administered after completion of all (neo)adjuvant chemotherapy and local treatment, including radiation therapy. 1, 2

Why Not Continue Pembrolizumab?

Pembrolizumab is FDA-approved for early-stage TNBC only as part of the neoadjuvant-to-adjuvant continuum when given WITH chemotherapy in the neoadjuvant phase. 3 The key distinction is:

• Pembrolizumab's indication in early-stage TNBC requires it to be given "in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery." 3

• If pembrolizumab was already given during neoadjuvant therapy with chemotherapy, continuing it post-surgery is the standard completion of that regimen. 3

• However, the question implies the patient received immunotherapy with chemotherapy neoadjuvantly and now faces a choice between pembrolizumab continuation versus starting olaparib.

Critical Evidence from OlympiA Trial

The OlympiA trial, which forms the basis for the ASCO recommendation, demonstrated:

• Significant improvement in invasive disease-free survival at 3 years: 85.9% with olaparib versus 77.1% with placebo (HR 0.58; P<0.001). 2

• Distant disease-free survival at 3 years: 87.5% with olaparib versus 80.4% with placebo (HR 0.57; P<0.001). 2

• These benefits were seen in gBRCA-mutated patients regardless of pCR status, though the trial was designed for high-risk patients. 1, 2

• Safety profile was manageable with no significant quality of life impairment. 1

Clinical Algorithm for This Patient

Step 1: Confirm Eligibility Criteria

• ✓ Triple-negative breast cancer 1
• ✓ Locally advanced disease (high-risk) 1
• ✓ Received neoadjuvant chemotherapy 1
• ✓ gBRCA1 or BRCA2 mutation confirmed 1, 2
• ✓ Achieved pCR after surgery 1

Step 2: Complete All Local Treatments First

• Ensure surgery is completed 1
• Complete all indicated radiation therapy before starting olaparib 1, 2
• If pembrolizumab was part of the neoadjuvant regimen and is being continued post-surgery, this should be completed according to the KEYNOTE-522 protocol (typically up to 9 cycles total or 1 year) 3, 4

Step 3: Initiate Olaparib

• Start olaparib 300 mg orally twice daily for 1 year 1, 2
• Begin after completion of radiation therapy 1
• Monitor for hematologic toxicities, particularly anemia 1

Important Caveats and Considerations

Sequencing Concerns

The OlympiA trial did not permit post-neoadjuvant capecitabine, and similarly did not evaluate sequencing with immunotherapy. 1 However:

• The guideline recommendation for olaparib is based on completion of standard (neo)adjuvant chemotherapy and local treatment. 1
• If the patient is still receiving adjuvant pembrolizumab post-surgery (as part of the KEYNOTE-522 regimen), complete this first before starting olaparib. 3, 4

Risk Despite pCR

Achieving pCR does not eliminate recurrence risk entirely, particularly in gBRCA-mutated TNBC. 4

• Case reports document early recurrence (within 7-15 months) even after pCR in TNBC patients. 4
• The KEYNOTE-522 study showed that even among patients with pCR, the hazard ratio for event-free survival favored the pembrolizumab group (HR 0.73), indicating residual risk. 4
• gBRCA mutation status confers both therapeutic vulnerability (to PARP inhibitors) and inherent genomic instability that justifies adjuvant olaparib even with pCR. 1, 2

Long-term Monitoring

• Follow-up for myelodysplastic syndrome and acute myelogenous leukemia is needed given PARP inhibitors are DNA-interacting drugs. 1
• Regular surveillance for disease recurrence should continue per standard guidelines. 1

What This Patient Should NOT Receive

Do not combine olaparib with pembrolizumab or other immunotherapy without clinical trial data supporting this combination. The evidence base for olaparib is as monotherapy following completion of standard treatments. 1, 2