A one-size-fits-all approach to treating patients with prostate cancer has limited efficacy. Facilitated largely by molecular biomarkers and biomarker testing, many patients with prostate cancer can now receive precision medicine. Data from clinical trials of precision medicine and biomarkers that could be used to determine the suitability of precision medicine were presented at the recent ESMO Congress 2024.

Following these proceedings, featured expert Andrew J. Armstrong, MD, MSc, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Armstrong’s clinical perspectives on these findings are presented here.

Most of the US Food and Drug Administration (FDA)–approved drugs that we have in prostate cancer are classic examples of imprecision medicine, meaning that there is no biomarker selection of patients to enrich for benefit. When you give a drug to a group of patients whose disease is defined by conventional imaging, prostate-specific antigen levels, castration resistance, or hormone sensitivity, there is no genetic, blood-based, or imaging biomarker. Enzalutamide, apalutamide, darolutamide, docetaxel, cabazitaxel, and radium, for example, all extend survival very successfully in unselected patients with prostate cancer. It is only relatively recently that we have had precision medicine drugs that extend survival in defined subsets of patients based on qualified biomarkers such as genetic tests or positron emission tomography (PET) imaging.

An example of precision medicine in prostate cancer are the PARP inhibitors. Olaparib, for example, extends survival as monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with mutated BRCA1 and BRCA2 but does not have the same dramatic activity in other subsets of patients who lack these genetic alterations.

Another example of precision medicine uses imaging biomarkers. Prostate-specific membrane antigen (PSMA) PET imaging identifies patients with prostate cancer who have the PSMA target on the cell surface. This, in turn, results in an improved progression-free survival (PFS) and overall survival when treated with ¹⁷⁷Lu-PSMA-617, as seen in the phase 3 VISION trial of men with PSMA PET–positive mCRPC in the post-ARPI and taxane settings. Such an approach was also tested in the recently published phase 3 PSMAfore trial testing this same treatment in chemotherapy-naive patients with mCRPC that was PSMA PET positive post ARPI. In addition, ¹⁷⁷Lu-PSMA-I&T is a novel PSMA-targeted radioligand therapy that was tested in the phase 3 SPLASH trial in patients with PSMA PET–positive mCRPC post ARPI, the results of which were presented at the ESMO Congress 2024 (abstract LBA65). SPLASH demonstrated a 3.5-month improvement in radiographic PFS as compared with a second ARPI, meeting the primary end point, but overall survival was not improved. The clinical meaning of these results is unclear, however, given the modest efficacy, and, while crossover was common, the lower dose and intensity of this approach as compared with ¹⁷⁷Lu-PSMA-617 trials suggest that dose and intensity do matter for radioligand therapies.

For precision immunotherapy, at this time we only have clear evidence for the efficacy of ICI success in selected patients with mCRPC with mismatch repair deficiency (MMRd)/microsatellite instability (MSI)–high tumors, which is only approximately 3% of those with prostate cancer. This was demonstrated in the phase 2 INSPIRE clinical trial presented at the ESMO Congress 2024, which assessed the efficacy and safety of combining the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab in patients with mCRPC (abstract LBA72). The INSPIRE trial found that patients with MMRd tumors had an improved antitumor response and survival compared with patients without MMRd tumors. This supports an earlier report presented at the 2024 ASCO Annual Meeting from the phase 2 NEPTUNES study, which reported that antitumor responses were enriched in patients with MMRd BRCA1/2 mutations, and the presence of high tumor-infiltrating lymphocyte levels with the combination of nivolumab and ipilimumab. These examples are just the most common and clinically actionable; there are many other examples in prostate cancer.

For instance, at this year’s ESMO Congress, updated results were reported with the CYP11 inhibitor opevesostat from the phase 2 CYPIDES trial (abstract 1605P). There was very clear antitumor activity with opevesostat in patients with AR-mutated mCRPC, but not as much activity in patients without AR mutations. Data remain fairly immature in terms of PFS, but this compound is now in phase 3 testing in mCRPC, overall and in AR ligand–binding domain mutation carriers.

Additionally, an ancillary study of the STAMPEDE trial testing whether a 22-gene mRNA score of gene expression for prostate cancer could predict benefit from docetaxel in patients with advanced prostate cancer receiving ADT was also presented at the ESMO Congress 2024 (abstract 1596O). Other prior work has shown a luminal B phenotype to be sensitive to docetaxel. Some clinicians in the United States currently use the 22-gene mRNA test for prostate cancer for prognostic purposes, although it is not cleared or approved by the FDA for predictive utility or the selection of systemic therapy for patients. Patients in this study with metastatic disease who had a high 22-gene mRNA score benefited from docetaxel, but I am not sure that we are going to be using the 22-gene mRNA score for prostate cancer based on this result. This is because we are now using triplet therapy, and the STAMPEDE trial was looking at doublet therapy with ADT plus docetaxel, a doublet that is no longer in common use, as compared with ADT alone. The study does, however, demonstrate a proof of principle, and this principle needs further validation in the context of triplet vs doublet therapy.

National guidelines now recommend germline and somatic tumor testing in all patients with metastatic prostate cancers to ensure that we find biomarkers such as BRCA1 and BRCA2 mutations and MSI-high disease, because precision medicine can lead to a patient living longer. Germline testing can be done with a blood or saliva sample, and it determines whether a mutation is hereditary. The purpose of germline testing is to determine why a patient got prostate cancer and whether there is a familial risk in children, siblings, or other relatives. Prostate cancer is commonly hereditary, with 57% of prostate cancer risk explained by genetics.

The other type of genetic testing is in tumor cells and identifies somatic mutations that may be unique to the tumor. It is important to realize that, when the BRCA1 gene is mutated, for example, it is a germline mutation 50% of the time and a tumor-specific mutation the other 50% of the time. In addition, somatic BRCA2 mutations are more common than germline mutations. So, if you only rely on germline testing, 50% of your patients would not be identified as potentially benefiting from a PARP inhibitor. The combination of a PARP inhibitor with an AR inhibitor was established from the PROpel and TALAPRO-2 trials to improve outcomes in the first-line mCRPC setting, particularly for those with germline or somatic DNA repair mutations such as BRCA1 and BRCA2.

There is real value in using precision medicine because it allows you to optimize the benefits of treatment, giving drugs to those patients who are most likely to benefit and avoiding toxicities from drugs that have no benefit in patients who lack biomarkers that are predictive of benefit.