SAHPRA Approval Trastuzumab Deruxtecan: Access & Affordability Insights

Key Takeaways

• Regulatory milestone: SAHPRA registered trastuzumab deruxtecan (registration 59/26/0013) on September 12, 2025, for HER2-positive and HER2-low metastatic breast cancer.
• Clinical breakthrough: The DESTINY-Breast04 trial demonstrated median progression-free survival of 9.9 months versus 5.1 months with chemotherapy in HER2-low disease.
• Market access gap: Despite regulatory approval, public sector access remains constrained by pricing and reimbursement challenges in South Africa.
• Mechanism: The antibody-drug conjugate delivers a topoisomerase I inhibitor payload directly to HER2-expressing cancer cells, enabling targeted therapy with reduced systemic exposure.

What Is Trastuzumab Deruxtecan?

Trastuzumab deruxtecan (marketed as Enhertu) is an antibody-drug conjugate (ADC) developed through a collaboration between AstraZeneca and Daiichi Sankyo. The drug combines a HER2-directed monoclonal antibody with a cleavable linker and a topoisomerase I inhibitor payload (deruxtecan).

The mechanism enables selective delivery of chemotherapy to cancer cells expressing HER2 receptors. Once bound to HER2, the conjugate undergoes internalization and intracellular linker cleavage, releasing the cytotoxic payload. This targeted approach aims to maximize anti-tumor activity while minimizing exposure to healthy tissues.

Dosing and Administration

The approved dosing regimen for trastuzumab deruxtecan is 5.4 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle). Treatment continues until disease progression or unacceptable toxicity occurs. The FDA prescribing information and SAHPRA-approved labeling recommend prophylactic antiemetic medications due to the drug's emetogenic potential.

What Did the SAHPRA Approval Cover?

SAHPRA's September 2025 registration encompasses two distinct indications for adult patients with breast cancer. The first covers unresectable or metastatic HER2-positive disease in patients who have received one or more prior anti-HER2-based regimens. The second—and clinically significant—approval extends to HER2-low metastatic breast cancer, defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization negative (ISH-).

The HER2-low designation represents a paradigm shift in breast cancer classification. Historically, patients with IHC 1+ or IHC 2+/ISH- tumors were classified as HER2-negative and ineligible for HER2-targeted therapies. The SAHPRA approval acknowledges the clinical utility of trastuzumab deruxtecan across this broader HER2 expression spectrum.

Registration Details

Parameter	Details
Registration Number	59/26/0013
Approval Date	September 12, 2025
Marketing Authorization Holder	AstraZeneca Pharmaceuticals (Pty) Limited
Manufacturer	Daiichi Sankyo Co., Ltd.
Presentation	100 mg powder for concentrate for solution for infusion

What Evidence Supports the HER2-Low Indication?

The HER2-low approval rests primarily on data from the Phase 3 DESTINY-Breast04 clinical trial. This randomized, open-label study enrolled 557 patients with HER2-low unresectable or metastatic breast cancer across 254 sites globally.

The trial population comprised 88.7% patients with hormone receptor (HR)-positive disease and 11.3% with HR-negative disease. Participants had received one to two prior lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival (PFS) in the HR-positive cohort, assessed by blinded independent central review.

Key Efficacy Outcomes

In the HR-positive population, trastuzumab deruxtecan achieved a median PFS of 10.1 months compared to 5.4 months with physician's choice chemotherapy (hazard ratio 0.51; 95% confidence interval 0.40–0.64; p<0.001). Median overall survival was 23.9 months versus 17.5 months, respectively (hazard ratio 0.64; 95% CI 0.48–0.86; p=0.003).

Across the overall trial population—including both HR-positive and HR-negative patients—the median PFS was 9.9 months versus 5.1 months (hazard ratio 0.50; 95% CI 0.40–0.63). Overall survival was 23.4 months versus 16.8 months (hazard ratio 0.64; 95% CI 0.49–0.84). The objective response rate was 52.3% with trastuzumab deruxtecan compared to 16.3% with chemotherapy.

How Does This Compare to Existing HER2 Therapies?

Trastuzumab deruxtecan enters a South African market with established HER2-targeted therapies, including trastuzumab (Herceptin) and pertuzumab (Perjeta). However, these agents require HER2-positive status—typically defined as IHC 3+ or IHC 2+/ISH+—for regulatory indication.

The HER2-low indication differentiates trastuzumab deruxtecan from earlier-generation agents. This expanded eligibility addresses a previously underserved patient segment. The DESTINY-Breast04 publication in the New England Journal of Medicine established this drug as the first HER2-directed therapy with demonstrated benefit in HER2-low disease.

For HER2-positive disease, the earlier DESTINY-Breast03 trial compared trastuzumab deruxtecan against trastuzumab emtansine (T-DM1) in patients previously treated with trastuzumab and taxane. Results showed median PFS of 28.8 months versus 6.8 months (hazard ratio 0.33), supporting the drug's positioning in later-line therapy.

What Safety Considerations Apply?

The FDA label carries a boxed warning for interstitial lung disease (ILD) and embryo-fetal toxicity. In DESTINY-Breast04, drug-related ILD occurred in 12.1% of patients receiving trastuzumab deruxtecan, with most events being low-grade (Grade 1–2). No Grade 4 or 5 ILD events were reported in this trial.

Other significant adverse events include neutropenia (13.7% Grade ≥3), anemia (8.1% Grade ≥3), and nausea (73.8% any grade, 4.6% Grade ≥3). The safety profile led to dose interruptions in 18.2% of patients and dose reductions in 15.1%. Treatment discontinuation due to adverse events occurred in 7.4% of patients.

SAHPRA's approved prescribing information mirrors these warnings, requiring monitoring for respiratory symptoms and appropriate management protocols for ILD. Healthcare providers must verify pregnancy status before initiating treatment given the teratogenic risk.

What Access Challenges Exist in South Africa?

Despite regulatory approval, patient access to trastuzumab deruxtecan in South Africa faces significant hurdles. The drug's position as a novel antibody-drug conjugate with complex manufacturing requirements contributes to a premium price point. This creates barriers to inclusion in public sector formularies.

South Africa operates a two-tiered healthcare system. Private medical insurance may provide coverage for eligible patients, while public sector access depends on national tender processes and essential medicines list inclusion. The timing of SAHPRA approval—September 2025—means the drug likely missed the 2025/2026 tender cycle, potentially delaying public sector availability.

AstraZeneca Pharmaceuticals (Pty) Limited holds the South African marketing authorization. The company's access strategies, including potential patient assistance programs or differential pricing agreements with the South African government, will influence real-world availability. Stakeholders should monitor pricing and reimbursement negotiations.

What Is the Global Regulatory Context?

The FDA granted accelerated approval for HER2-low breast cancer on August 5, 2022, based on DESTINY-Breast04 data. This represented the first regulatory authorization for HER2-low disease globally. The European Medicines Agency (EMA) followed with a positive opinion later in 2022.

SAHPRA's September 2025 approval positions South Africa among the earlier African nations to register the indication, though the timeline reflects a typical lag for innovative oncology agents entering middle-income markets. The registration demonstrates alignment between SAHPRA's evaluation and major regulatory authorities, facilitating the reliance pathways increasingly utilized for medicine registration in Africa.

Frequently Asked Questions

Primary Sources

1. South African Health Products Regulatory Authority. Enhertu 100 mg powder for concentrate for solution for infusion: Registration 59/26/0013. Approved September 12, 2025. SAHPRA Register
2. U.S. Food and Drug Administration. Highlights of Prescribing Information: Enhertu (fam-trastuzumab deruxtecan-nxki). January 2025. FDA Label [PDF]
3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387(1):9-20. NEJM Publication
4. ClinicalTrials.gov. DESTINY-Breast04: Trastuzumab Deruxtecan Versus Physician's Choice Chemotherapy. NCT03529110. Trial Record
5. U.S. Food and Drug Administration. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. August 5, 2022. FDA Announcement