The next innovation for PARP inhibitors will likely involve combinations with other DNA-damaging agents beyond just ARPIs. Promising partners include radioligands like radium (an alpha emitter) and lutetium, or even therapies like superphysiologic testosterone (BAT) that are theorized to work by inducing DNA breaks.
If lutetium-PSMA is approved and used upfront in hormone-sensitive disease, clinicians may become more comfortable with radioligands generally. This could lead them to use the enzalutamide-radium combination more frequently later on, paradoxically increasing radium's use by flipping the current treatment sequence.
While BRCA2 mutations are typically associated with aggressive prostate cancer, this is not universal. Clinical experience reveals a subset of BRCA2 patients with surprisingly indolent disease, even without PARP inhibitors. This suggests other clinical or molecular factors are at play, challenging a one-size-fits-all treatment approach.
A nuanced approach to PARP inhibitors involves reserving combinations for BRCA2 patients with clear, aggressive clinical features like high-volume disease or liver metastases. This strategy balances potent efficacy against toxicity for a molecularly defined but clinically heterogeneous group, avoiding overtreatment of those with more indolent disease.
A key lesson from radium-223 trials is the critical need for concurrent bone protective agents. Protocol amendments adding these agents eliminated an excess of osteoporotic fractures. This requires only osteoporosis prevention dosing (e.g., yearly zoledronic acid), not the more frequent dosing used for skeletal-related events.
The BREAKAWAY trial's OS data is from a small, crossover-allowed study, making it hard to interpret alone. However, its findings are believable because they align with and reinforce a "building body of evidence" from larger trials like PROPEL and TALA PRO 2, which also show a survival benefit for PARP inhibitor combinations.
Clinicians may be biased towards lutetium-PSMA because it causes significant PSA drops, which radium-223 does not. This observable metric may not reflect superior overall efficacy, as radium's survival benefit is proven and it may even have unique synergistic potential with drugs like enzalutamide through different biological pathways.
The PEACE-3 steering committee felt its initial positive OS signal was unreliable due to non-proportional curves, despite meeting the statistical goal. This suggests a high level of self-imposed rigor, as early curve crossing can be due to statistical chance when event numbers are low, rather than a true lack of benefit.