Castration-Resistant Prostate Cancer: Molecular and Genomic Subtypes
Genomic heterogeneity is frequently observed in advanced prostate cancer. Featured expert Oliver Sartor, MD, reviews the progress in precision medicine for patients with castration-resistant prostate cancer (CRPC), noting therapies in development that would use prostate-specific membrane antigen (PSMA) expression as a predictive biomarker.
C. E. and Bernadine Laborde Professor of Cancer Research
“Molecular and genetic heterogeneity is being further explored, and there will be increasing relevance for these findings as they are incorporated more broadly into clinical practice.”
One of the things that we can do in patients with CRPC is to test the germline. This is very easy, as it can be done with a blood draw, and there are a variety of companies that do it. A couple of biomarkers, including BRCA1 and BRCA2, can be predictive. The poly (ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib are both approved by the US Food and Drug Administration (FDA) within the context of germline mutations in BRCA. Further, germline testing can have implications for the family beyond the predictive biomarker.
In addition to the PARP inhibitors, we have pembrolizumab, which is approved for mismatch repair–deficient tumors. I have an extraordinary case right now involving a patient who had a very unusual alteration in the MSH2 gene in the germline and in the tumor. We started him on pembrolizumab, and he subsequently went into complete remission; in fact, we were ultimately able to stop his androgen deprivation therapy. It was amazing. This is a patient who had metastatic CRPC (mCRPC) and had already been treated with docetaxel and abiraterone. Having such an excellent outcome with pembrolizumab is unusual, but it shows the great potential of treating these molecularly defined disease subsets.
Although obtaining tissue samples from the tumor for testing can be a bit more challenging than blood-based germline testing, we can find an additional percentage of patients who end up having a somatic mutation in BRCA1 or BRCA2, even though that mutation was not present in the germline. We can identify the mismatch repair genes, including MSH2 and MSH6, and patients with these mutations can respond quite well to pembrolizumab. We can also find other homologous recombination genes that serve as predictive biomarkers, including PALB2.
Thus, as of June 2021, we have the following 3 FDA-approved agents for the treatment of select molecular subsets of mCRPC: the PARP inhibitors olaparib and rucaparib and the immune checkpoint inhibitor pembrolizumab. The FDA has approved companion diagnostics for both rucaparib and olaparib for BRCA1, BRCA2, and ATM mutations; so, now we have FDA approvals for circulating tumor DNA to serve as a predictive biomarker for the use of the PARP inhibitors. We are working in prostate cancer beyond BRCA1, BRCA2, and ATM, but those are currently the only FDA approvals.
Molecular and genetic heterogeneity is being further explored, and there will be increasing relevance for these findings as they are incorporated more broadly into clinical practice. For instance, if you express PSMA, you could respond to PSMA-targeted therapies. We have been talking quite a bit about lutetium-177–PSMA-617 following the recent 2021 American Society of Clinical Oncology Annual Meeting, and there are several PSMA-targeted radioligands in various phases of clinical development, including some alpha emitters such as the alpha emitter 225Ac. So, we are looking at different isotopes and different molecules. PSMA is also being investigated as a form of immunotherapy using bispecific antibodies.
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