Combination therapies involving lutetium-PSMA are showing promise in enhancing prostate cancer treatment, particularly in advanced stages. The approach aims to improve outcomes by targeting different clonal populations within tumors and overcoming resistance mechanisms.
Hormonal Therapy Combinations
Louise Emmett and Oliver Sartor discussed the rationale and results of combining lutetium-PSMA with hormonal therapies. Lutetium-PSMA alone is effective in only about one-third of men, prompting the need for combination strategies to address the remaining two-thirds. The androgen receptor and PSMA receptor pathways are both active targets, making the combination of androgen receptor pathway inhibitors (ARPIs) and lutetium-PSMA a logical approach.
The ENZA-p trial, which combined lutetium-PSMA with enzalutamide in first-line mCRPC, demonstrated a significant improvement in PSA progression-free survival (PFS) compared to lutetium-PSMA alone (13 months vs. 7.8 months). Notably, the combination therapy achieved an 80% PSA response rate. Overall survival data from the ENZA-p trial is expected to be presented at an upcoming ASCO GU meeting.
Other Combination Strategies
Beyond hormonal therapies, researchers are exploring combinations with PARP inhibitors, taxanes, and immunotherapies. PARP inhibitors may enhance the effects of lutetium-PSMA by disrupting DNA repair mechanisms in cancer cells. Michael Hofman and his team at ProsTIC are conducting the LuCaP trial, which combines lutetium-PSMA with cabazitaxel, a taxane, to improve treatment outcomes in mCRPC.
Immunotherapy combinations are also under investigation. Shahneen Sandhu is leading the Evolution trial, which combines lutetium-PSMA with ipilimumab and nivolumab. However, the trial was stopped early due to toxicity concerns, highlighting the importance of rational and well-tolerated combinations.
Adaptive Dosing and Future Directions
Adaptive dosing strategies are being explored to optimize treatment based on individual patient responses and disease characteristics. This approach involves adjusting the dose and timing of lutetium-PSMA based on the presence and activity of the target. The goal is to maximize efficacy while minimizing toxicity and prolonging disease control.
Looking ahead, research is focused on identifying the most effective combinations for different disease states and patient populations. Factors such as disease stage, prior treatments, and individual patient characteristics will likely play a role in determining the optimal treatment strategy. The integration of novel imaging techniques and biomarkers may also help to personalize treatment and improve outcomes.
