It is still in the early days for biomarker-driven therapeutics in prostate cancer, but the data presented at the ESMO Congress 2021 continue to add to the knowledge base in metastatic castration-resistant prostate cancer (mCRPC). We have 2 US Food and Drug Administration (FDA)–approved PARP inhibitors in the United States: olaparib and rucaparib.

What we saw at the meeting was quite a bit of early work exploring variations of a theme using other PARP inhibitors such as niraparib alone or in combination with agents such as pembrolizumab. The FDA-approved PARP inhibitors have their most significant activity in patients with BRCA2 and BRCA1 mutations, and, perhaps to a lesser extent, in those with ATM mutations. Further, although a recent press release suggests that the olaparib-plus-abiraterone combination improves radiographic progression-free survival in men with mCRPC in the phase 3 PROpel study, we have limited data on the use of other PARP combinations. So, from a biomarker-driven therapy perspective, there is clearly more work to be done here.

PTEN loss is a predictive biomarker for AKT inhibition, another important molecular target in mCRPC. The phase 3 IPATential150 trial exploring combination therapy with the AKT inhibitor ipatasertib plus abiraterone was not a positive study, as it was originally intended; however, there was apparent activity in patients who had evidence of PTEN loss. Some of the safety data were reported by Sternberg and colleagues at the ESMO Congress 2021 (abstract 585P). While this combination does seem to have activity, there is a fair amount of toxicity associated with this regimen. So, a lot more research is needed in this space. Further, as noted above, the recent preliminary data from the PROpel trial are provocative, and we await a presentation of these data at an upcoming scientific congress, along with overall survival data.

Another biomarker that is really gaining attention is PSMA, which is a theranostic molecular biomarker, meaning that it is useful in both imaging and therapeutics. PSMA positron emission tomography/computed tomography has been regulatorily approved by the FDA in the United States and will probably replace conventional imaging because of its sensitivity and specificity. There are several PSMA-targeted radioligand therapeutic molecules in this space, but lutetium-177–PSMA-617 is receiving the most attention, as it is the furthest along in development. It has been tested in the phase 3 VISION study, which demonstrated a survival benefit. Trials in progress include the randomized phase 3 PSMAddition study (abstract 647TiP), which is investigating targeted radioligand therapy in mCRPC, and the randomized phase 3 PSMAfore study (abstract 648TiP), which is looking at taxane-naive patients with progressive mCRPC and confirmed PSMA expression. Additionally, interim data from the phase 1b PRINCE trial were presented at the ESMO Congress 2021, wherein lutetium and pembrolizumab were combined (abstract 5770). 

It should be noted that PSMA is expressed at some level in approximately 85% of patients; thus, it is a potentially broadly viable target. In the near term, there are a number of important questions that need resolution. For instance, will demonstrating PSMA positivity by positron emission tomography/computed tomography be required for lutetium use, based on an FDA-approved label? Additionally, we would like to know whether we can upregulate PSMA expression in the tumor and whether that can be used to improve outcomes. Many people who work in this space recognize that we are very early in this exploration, and, even though our Australian and European colleagues have been using this agent in a variety of settings for several years now, much more work needs to be done. That said, this area holds great promise, and I will be following developments here closely.