Andrew J. Armstrong, MD, MSc: When you’re assessing a patient who has progressive mCRPC [metastatic castration-resistant prostate cancer], there are many prognostic factors. Prognostic factors tell you more about the natural history of a patient and how they’re going to do on systemic therapy regardless of which treatment you pick. Liver metastases, pain, performance status, Gleason score, the volume of bone metastases, PSA [prostate-specific antigen] levels, circulating tumor cell count, and cell-free DNA concentrations are examples of prognostic biomarkers.

There are also predictive biomarkers. If a patient has had a prior AR [androgen receptor] inhibitor, the AR-V7 [androgen receptor splice variant 7] circulating tumor cell assay has been both prognostic, meaning it’s associated with poor prognosis, but it’s also potentially predictive of the benefits of a taxane rather than a second AR inhibitor. That’s an example of where we use different terms like predictive vs prognostic, and that can help with treatment decision-making.

Other predictive biomarkers could include the pattern of spread. For example, we tend to recommend docetaxel in patients with liver metastases, or a biopsy to look for small cell neuroendocrine transformation. That could be helpful in patients with symptomatic bone metastases. Radium-223 may be an appropriate option after failure of an AR therapy. But in general, the algorithm for patients with mCRPC in the front line, if they haven’t already had an AR inhibitor, is to consider ADT [androgen deprivation therapy] plus an AR inhibitor, like abiraterone or enzalutamide. If they’ve already had an AR inhibitor in the hormone-sensitive disease setting, then a second AR inhibitor generally isn’t very effective and isn’t associated with improved survival, so we tend to pick a different mechanism of action to attack that cancer and improve the survival of patients, such as a taxane or radium.

We undergo molecular profiling for that patient, either germline or somatic tumor profiling, or both, to understand what other options may be available, such as a PARP inhibitor or a PD-1–based therapy. There are some emerging data from the 2022 ASCO Genitourinary Cancers Symposium that suggest, particularly in patients with BRCA1 or BRCA2 and other HRD [homologous recombination deficiency] mutations, that the combination of olaparib plus abiraterone, or niraparib plus abiraterone, may extend progression-free survival, particularly in HRD-positive patients. In the PROpel study, we showed that in unselected patients, there was a significant improvement in progression-free survival over abiraterone alone, but there’s a greater magnitude of benefit with the PARP-abiraterone combinations if you’re HRD-positive, particularly if you’re BRCA1- or BRCA2-positive. These are substantial delays [in disease progression], where in the future we may be using abiraterone plus a PARP inhibitor as a frontline therapy for these patients.

Transcript edited for clarity.