While pirtobrutinib works after covalent BTK inhibitors, no data shows covalent inhibitors work after pirtobrutinib failure. This uncertainty about future options makes clinicians cautious about using it as an initial therapy, especially for younger CLL patients who will need multiple treatments over their lifetime.

Non-covalent BTK inhibitors like pirtobrutinib are currently approved for use after covalent BTK inhibitors fail. Moving them to the frontline setting, as studied in BRUIN-313, disrupts the established treatment pathway and creates uncertainty for managing relapsed disease, as the standard 'next step' is removed.

Pirtobrutinib is the first BTK inhibitor to show a rate of atrial fibrillation equivalent to a chemoimmunotherapy control arm in a randomized trial. This uniquely safe cardiovascular profile makes it a strong first-line candidate for older Chronic Lymphocytic Leukemia (CLL) patients or those with significant heart-related comorbidities.

For patients with oligometastatic disease who achieve a deep PSA response (e.g., to zero), oncologists consider finite treatment durations (e.g., 18-24 months) followed by observation. This "do less harm" approach challenges the standard of continuous therapy until progression, aiming for long-term treatment-free intervals.

The common practice of switching from one ARPI to another upon disease progression is now considered ineffective for most patients. With the advent of proven alternatives like chemotherapy and lutetium, using an "ARPI switch" as the sole control arm in clinical trials is no longer ethically or scientifically sound.

The BRUIN-313 trial successfully compared pirtobrutinib to bendamustine-rituximab (BR). However, BR is no longer the frontline standard of care. This 'straw man' comparator makes it difficult to position pirtobrutinib against current preferred treatments like other BTK inhibitors or venetoclax regimens, limiting immediate clinical applicability.

Despite strong single-agent trial results, experts believe the field is shifting away from continuous monotherapy. The most significant future impact for pirtobrutinib will likely be as a backbone of fixed-duration combination therapies with drugs like venetoclax, aiming for deeper remissions without indefinite treatment.

While pirtobrutinib is effective after covalent BTK inhibitors, the reverse is unproven. Starting with pirtobrutinib frontline raises a critical unanswered question about whether patients will still respond to older covalent inhibitors, complicating sequencing decisions, especially for younger patients.

Pirtobrutinib's registrational trials used control arms (ibrutinib, bendamustine-rituximab) that are no longer the standard of care in the US. This strategy reflects the long timeline of trial design and the need to use comparators that are still considered a standard globally, ensuring broader regulatory acceptance and allowing for cross-trial comparisons.