The introduction of ADCs into frontline ovarian cancer treatment creates a new challenge: conflicting biomarkers. A patient's tumor might be positive for both HER2 (an ADC target) and a BRCA mutation (a PARP inhibitor target), forcing clinicians to choose between two effective targeted therapies without clear guidance.

The clinical strategy of 'saving' the most effective drugs for later lines of therapy may be flawed. Data indicates that 20-30% of patients with metastatic breast cancer do not go on to receive a subsequent line of treatment after progression, arguing for the use of optimal therapies like ADCs earlier in the disease course.

After a triple-negative breast cancer patient progresses on a first-line TROP2 antibody-drug conjugate (ADC), experts advise against immediately sequencing another ADC. Due to suspected cross-resistance, the recommended strategy is to return to traditional chemotherapy agents like taxanes or carboplatin, which remain effective options, before considering another ADC in later lines.

In the absence of direct evidence for adjuvant therapy in high-risk, non-clear cell kidney cancers, clinicians may justify off-label treatment by extrapolating from the drug's known efficacy in the metastatic setting for that specific histology. This highlights the difficult risk-benefit calculations made daily in data-poor clinical scenarios.

Retrospective data shows that using one Antibody-Drug Conjugate (ADC) after another, particularly those with the same class of payload like TOP1 inhibitors, results in a low response rate of 10-20%. This creates a significant unmet need and a major clinical challenge for patients who progress on a first-line ADC.

Clinicians face a strategic dilemma where using an ADC off-label for a patient with a low-expressing biomarker (e.g., TDXD for HER2 1+) could provide benefit but also render that patient ineligible for a future clinical trial of a potentially more effective ADC. This highlights a tension between immediate access and optimizing long-term treatment sequencing.

Unlike the US, where Phase 2 trial data can support flexible use of drug combinations, European practice varies significantly. The UK strictly adheres to drug labels, while countries like Germany allow for more flexibility based on updated national guidelines and specific clinical contexts.

Emerging data shows that a second ADC, particularly one with the same payload, often has limited efficacy. This suggests clinicians must be highly strategic in selecting the first ADC, as it may be their most impactful opportunity for this class of drugs.

As multiple effective Antibody-Drug Conjugates (ADCs) become available, the primary clinical challenge is no longer *if* they work, but *how* to use them best. Key unanswered questions involve optimal sequencing, dosing for treatment versus maintenance, and overall length of therapy, mirroring issues already seen in breast cancer.