SAHPRA Approval Trastuzumab Deruxtecan: What You Need to Know
SAHPRA has approved Trastuzumab Deruxtecan, a groundbreaking therapy for HER2-positive breast cancer, offering new hope for patients.
Quick Answer
SAHPRA has approved Trastuzumab Deruxtecan, a groundbreaking therapy for HER2-positive breast cancer, offering new hope for patients.
Key Questions
- What is trastuzumab deruxtecan and how does it work?
- Which breast cancer patients qualify for trastuzumab deruxtecan under SAHPRA approval?
- What clinical evidence supports SAHPRA's approval of trastuzumab deruxtecan?
- What safety concerns does SAHPRA highlight for trastuzumab deruxtecan?
- How does SAHPRA's approval compare to FDA and EMA decisions?
The South African Health Products Regulatory Authority (SAHPRA) approved trastuzumab deruxtecan (Enhertu) for treating HER2-positive and HER2-low metastatic breast cancer, becoming the first MEA regulator to authorize the antibody-drug conjugate for both indications based on DESTINY-Breast03 and DESTINY-Breast04 trial results.
Contents9 sections
Key Takeaways
- Dual indication approved: SAHPRA authorized trastuzumab deruxtecan for HER2-positive and HER2-low metastatic breast cancer in adult patients, citing a 72% reduction in disease progression risk versus trastuzumab emtansine in the DESTINY-Breast03 trial (SAHPRA, 2025).
- HER2-low breakthrough: The HER2-low approval addresses a previously underserved population, with DESTINY-Breast04 showing median overall survival of 22.9 months versus 16.8 months with chemotherapy (Nature Medicine, 2025).
- Safety warnings issued: SAHPRA mandates permanent discontinuation for Grade 2 or higher interstitial lung disease and warns of embryo-fetal toxicity requiring contraception during treatment (SAHPRA, 2025).
- Regional access expanded: The approval positions South Africa as a leading MEA market for advanced antibody-drug conjugates, with potential influence on treatment access across the region.
What Did SAHPRA Approve?
SAHPRA granted marketing authorization for trastuzumab deruxtecan (brand name Enhertu) in November 2025. The official prescribing information specifies two distinct therapeutic indications for adult patients with breast cancer.
First, SAHPRA approved the drug for patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens. HER2-positive status requires immunohistochemistry (IHC) 3+ or IHC 2+ with positive in situ hybridization (ISH) testing.
Second, and more notably, SAHPRA approved trastuzumab deruxtecan for HER2-low breast cancer. This category includes patients with IHC 1+ or IHC 2+/ISH-negative disease who received prior chemotherapy in the metastatic setting or experienced disease recurrence within 6 months of completing adjuvant chemotherapy. This expanded indication represents a regulatory shift, as HER2-low patients previously lacked targeted therapy options.
The medicine is classified as Schedule 4 (S4), meaning it requires prescription by a healthcare provider and administration under supervision of a professional experienced in anticancer medicines. The 100 mg vial contains approximately 8 molecules of deruxtecan attached to each antibody molecule via a tetrapeptide-based cleavable linker.
What Clinical Evidence Supports the Approval?
SAHPRA's decision rests on data from two pivotal phase 3 trials: DESTINY-Breast03 for HER2-positive disease and DESTINY-Breast04 for HER2-low disease. Both trials were randomized, multicenter studies sponsored by Daiichi Sankyo and AstraZeneca.
DESTINY-Breast03: HER2-Positive Results
The DESTINY-Breast03 trial enrolled 524 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned to receive trastuzumab deruxtecan or trastuzumab emtansine (T-DM1), the prior standard of care.
The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. At 12 months, 75.8% of patients receiving trastuzumab deruxtecan remained alive without disease progression versus 34.1% in the T-DM1 group. The hazard ratio for progression or death was 0.28 (95% confidence interval, 0.22 to 0.37; P<0.001), representing a 72% reduction in risk.
The median PFS was not reached in the trastuzumab deruxtecan group versus 6.8 months with T-DM1. Overall response rate was 79.7% versus 34.2%, respectively. Twelve-month overall survival was 94.1% versus 85.9% (hazard ratio for death, 0.55).
DESTINY-Breast04: HER2-Low Results
The DESTINY-Breast04 trial focused on HER2-low metastatic breast cancer, defined as IHC 1+ or IHC 2+/ISH-negative. This population had no approved targeted therapies prior to this trial. Patients were randomized to trastuzumab deruxtecan or physician's choice of chemotherapy.
After a median follow-up of 32.0 months, median overall survival in the overall cohort was 22.9 months for trastuzumab deruxtecan versus 16.8 months for chemotherapy (hazard ratio 0.69; 95% CI 0.55–0.86). For the hormone receptor-positive subgroup, median overall survival was 23.9 months versus 17.6 months (hazard ratio 0.69).
How Is the Drug Administered?
Trastuzumab deruxtecan is administered as an intravenous infusion once every three weeks. The SAHPRA prescribing information specifies:
- Initial infusion: 90 minutes
- Subsequent infusions: 30 minutes if the first infusion is tolerated
- Dosing: Based on patient weight (5.4 mg/kg for HER2-low; 5.4 mg/kg for HER2-positive)
- Schedule: Every 3 weeks (21-day cycle)
Patients require premedication with antipyretics and antihistamines to reduce infusion-related reactions. Healthcare providers must monitor patients during and after infusion for fever, chills, and other signs of hypersensitivity.
What Are the Key Safety Concerns?
SAHPRA's prescribing information carries two black-box warnings. The first addresses interstitial lung disease (ILD) and pneumonitis. These events occurred in 10.5% of patients in DESTINY-Breast03 versus 1.9% with T-DM1. SAHPRA mandates permanent discontinuation for Grade 2 or higher ILD. Providers must monitor for cough, dyspnea, fever, and new respiratory symptoms.
The second warning covers embryo-fetal toxicity. Exposure during pregnancy can cause fetal harm. SAHPRA requires effective contraception during treatment and for 7 months after the last dose for female patients, and for 4 months after for male patients with female partners.
Common adverse reactions (occurring in >20% of patients) include nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Neutropenia occurred in 19% of patients, with 16% experiencing Grade 3 or 4 events.
How Does SAHPRA's Decision Compare to Global Regulators?
SAHPRA's approval aligns with decisions by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), though timing varies:
| Regulator | HER2-Positive Approval | HER2-Low Approval |
|---|---|---|
| FDA (United States) | 2019 | August 2022 |
| EMA (European Union) | January 2021 | July 2022 |
| SAHPRA (South Africa) | November 2025 | November 2025 |
The FDA granted accelerated approval for HER2-low breast cancer in August 2022 based on DESTINY-Breast04 results. The EMA's Committee for Medicinal Products for Human Use followed with a positive opinion in July 2022, leading to European Commission authorization.
SAHPRA's November 2025 approval for both indications simultaneously reflects the agency's review of the complete clinical dataset and positions South Africa among the first MEA markets with access to this therapy for both HER2-positive and HER2-low disease.
What Does This Mean for Patients in South Africa?
The SAHPRA approval enables oncologists in South Africa to prescribe trastuzumab deruxtecan for eligible patients. This marks a significant step forward for oncology care in the region. However, regulatory approval does not guarantee immediate patient access. Several factors influence availability:
Reimbursement: South Africa's public and private healthcare sectors must make reimbursement decisions. The public sector, serving the majority of the population through the Department of Health, faces budget constraints that may delay formulary inclusion.
Pricing: The manufacturer's pricing strategy for the South African market will affect uptake. Antibody-drug conjugates typically command premium prices, and negotiations with payers may be required.
Diagnostics: HER2 testing infrastructure must support accurate identification of HER2-low patients. This requires pathology laboratories equipped for immunohistochemistry and in situ hybridization testing.
Supply chain: Cold chain logistics are required for the lyophilized powder, which must be reconstituted and administered under sterile conditions.
The approval strengthens South Africa's position as a regulatory leader in the MEA region. Other national regulators in Africa and the Middle East often reference SAHPRA decisions when evaluating new medicines.
Frequently Asked Questions
What is trastuzumab deruxtecan and how does it work?
Trastuzumab deruxtecan (Enhertu) is an antibody-drug conjugate (ADC) that combines a HER2-targeting antibody with a topoisomerase I inhibitor payload called DXd. It binds to HER2 receptors on cancer cells, enters the cells, and releases chemotherapy directly inside. This targeted delivery reduces harm to healthy tissue and enables efficacy in HER2-low tumors where conventional HER2 therapies fail.
Which breast cancer patients qualify for trastuzumab deruxtecan under SAHPRA approval?
SAHPRA approved trastuzumab deruxtecan for two groups: (1) adults with unresectable or metastatic HER2-positive breast cancer who received prior anti-HER2 therapy, and (2) adults with HER2-low breast cancer (IHC 1+ or IHC 2+/ISH-negative) who received prior chemotherapy for metastatic disease or relapsed within 6 months of adjuvant chemotherapy. HER2 status requires testing via immunohistochemistry and/or in situ hybridization.
What clinical evidence supports SAHPRA's approval of trastuzumab deruxtecan?
SAHPRA's approval rests on DESTINY-Breast03 and DESTINY-Breast04 trials. DESTINY-Breast03 showed a 72% reduction in disease progression risk versus trastuzumab emtansine in HER2-positive disease (HR 0.28). DESTINY-Breast04 demonstrated median overall survival of 22.9 months versus 16.8 months with physician's choice chemotherapy in HER2-low disease (HR 0.69).
What safety concerns does SAHPRA highlight for trastuzumab deruxtecan?
SAHPRA's prescribing information warns about interstitial lung disease (ILD) and pneumonitis, including fatal cases. The agency requires permanent discontinuation for Grade 2 or higher ILD. Embryo-fetal toxicity is also flagged, requiring effective contraception during treatment. The most common adverse events include nausea, fatigue, vomiting, and alopecia.
How does SAHPRA's approval compare to FDA and EMA decisions?
SAHPRA's approval aligns with FDA and EMA authorizations for both HER2-positive and HER2-low indications. The FDA approved trastuzumab deruxtecan for HER2-positive disease in 2019 and HER2-low disease in 2022. The EMA authorized both indications through the European Commission. All three agencies reviewed the same DESTINY-Breast03 and DESTINY-Breast04 data, though SAHPRA applies South African regulatory standards.
Primary Sources
- South African Health Products Regulatory Authority (SAHPRA). Enhertu 100 mg powder for concentrate for solution for infusion: Professional Information. SAHPRA Product Information Repository. November 2025. Available at: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2025/11/pi-approved-4.pdf
- Cortés J, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. New England Journal of Medicine. 2022;386(12):1143-1154. DOI: 10.1056/NEJMoa2115022
- Modi S, et al. Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial. Nature Medicine. 2025;31:2732-2739. DOI: 10.1038/s41591-025-03981-4
- European Medicines Agency. Enhertu: EPAR - Medicine Overview. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/enhertu
- Daiichi Sankyo and AstraZeneca. ENHERTU Approved in the EU for Patients with HER2 Positive Metastatic Breast Cancer. Press Release. July 19, 2022. Available at: https://www.daiichisankyo.com/files/news/pressrelease/pdf/202207/20220719_E2.pdf
- U.S. Food and Drug Administration. FDA Approves Trastuzumab Deruxtecan for HER2-Low Breast Cancer. August 5, 2022. Available at: FDA Drug Approvals Database
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