Benefits of these targeted agents are not limited to tumours with germline BRCA1/2 mutations, but many questions remain to be answered
As oncologists, our perpetual challenge is to be at the forefront of transformative research that redefines patient care. In breast cancer treatment, poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors have been heralded as part of the vanguard of precision medicine, but the population of patients who derive a substantial benefit from these agents is still limited.
PARP inhibitors have been groundbreaking for patients with germline BRCA1/2 mutations, representing the first agents approved selectively. As highlighted in a recent review exploring their role in clinical practice, the implications are profound: not merely as a treatment, but as a beacon of personalised medicine that leverages the Achilles' heel of hereditary cancers (JAMA Oncol. Published online March 21, 2024). However, the landscape is nuanced as resistance to these agents, much like the mythological Hydra, inevitably emerges in almost all patients thus representing a complex clinical problem to be addressed.
Evidence from recent studies suggests the benefit of PARP inhibitors is not confined to patients with germline BRCA1/2 mutations alone, and somatic mutations and germline PALB2 alterations also appear to be responsive to these agents. Importantly, this widens the therapeutic net, offering options beyond the metastatic context, in the adjuvant setting - though with the caveat that metastatic breast cancer patients do not often achieve long-term benefits observed in other cancers.
However, there is a need to progress further in research. Our focus must pivot to identifying predictive biomarkers for PARP inhibitor response and novel combination strategies to address resistance. What is clear is that our traditional therapeutic strategies require recalibration, and this includes integrating PARP inhibitors with existing treatments, such as chemotherapy, immunotherapy, and emerging antibody-drug conjugates. Also, the toxicity profile of PARP inhibitors, notably myelotoxicity, cannot be understated, it is a clear limitation that requires clinicians’ attention.
Although challenging, the future of PARP inhibitors is a bright one. The path forward is paved with questions that demand our attention and clinical acumen. Today, we face a dual call to action: firstly, to integrate this evolving knowledge into nuanced, patient-specific treatments; secondly, to relentlessly pursue the research pathways that will lead us to outpace the development of resistance. As we wield these novel tools, let's step forward with a cautious optimism that honours both the complexity of science and the lives of those we aim to heal.
