Reviewing Various Biomarker Settings for Patients with Prostate Cancer

Kara N. Maxwell, MD, PhD, expanded upon the available biomarkers for use in prostate cancer in a presentation during the 21st Annual Meeting of the Society of Urologic Oncology (SUO). She explained how the available biomarkers can be applied at various points, while also guiding toward which treatments can improve patient care.

Maxwell, an assistant professor in the Departments of Medicine-Hematology/Oncology and Genetics, Penn Medicine, explained that with any type of cancer, biomarkers can fall into several different categories: biomarkers of risk, diagnostic biomarkers, and prognostic and predictive biomarkers for treatment. “Many of these categories are starting to blend [in prostate cancer],” she commented.

“Things have gotten very confusing in the biomarker space when we think about genomics, and it's very important when you're thinking about treating your patient with one of these therapies to think carefully about the test that you’ve ordered.”

Risk Biomarkers

Risk biomarkers entail germline genetic factors that predetermine that a man is at risk for developing prostate cancer. Maxwell explained that these mutations range from common single nucleotide polymorphisms that do not carry a significant risk of cancer to the more rare but traditional cancer genes, such as BRCA1/2, that are associated with a more significantly increased risk of cancer. She noted that HOXB13 G84E is also associated with a 2 to 3 times increased risk of prostate cancer.

Several of these risk biomarkers have prognostic and predictive value as well, including BRCA2.

“Things have really expanded and changed in the germline world with a number of different companies offering tests. And really [this] is to make the point that…as a practicing clinician, one cannot assume what genes your patients have been tested for unless you actually see the test that they underwent,” she commented.

Diagnostic Biomarkers

Diagnostic biomarkers in prostate cancer typically include prostate-specific antigen (PSA) level testing, but testing is also ongoing for several urine and tissue-based biomarkers. These biomarkers can also potentially be used in treatment monitoring, and the prognostic value of these markers continues to be explored.

Prognostic/Predictive Biomarkers

Maxwell explained that since a landmark article was published in Cell in 2015 defining many of the genomic alterations commonly found in metastatic prostate cancer,² many biomarkers have been more defined in prostate cancer and incorporated into guidelines for recommended genomic testing. Most research since then has focused on alterations in DNA repair mechanisms that can be targeted with genomically-targeted therapies, like PARP inhibitors.

Olaparib (Lynparza) is an FDA-approved PARP inhibitor for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who harbor deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations and have progressed on prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga). The approval was based on findings from the phase 3 PROfound trial (NCT02987543).³

The companion diagnostics approved for use with olaparib are the FoundationOne CDx for somatic mutations and the Myriad BRACAnalysis CDx for germline mutations. This Myriad test also evaluated homologous recombination deficiency in patients who are negative for germline mutations.

In the trial, patients were tested for HRR gene mutations for inclusion in the study of BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L using the FoundationOne CDx assay. In PROfound, responses did vary according to the gene alterations, with patients with BRCA1 (HR, 0.41) and BRCA2 (HR, 0.21) showing significant benefit from olaparib whereas those with PPP2R2A did not demonstrate a benefit from treatment with the PARP inhibitor (HR, 6.61).

“It is important to note that this is somatic-only testing and does not distinguish whether or not these patients carry germline or somatic mutations, and notably, also did not distinguish whether or not they may carry mutations in their lymphocytes by a process known as clonal hematopoiesis of indeterminate potential [CHIP],” Maxwell said. “However, going with the assumption that most of these are either tumor or germline mutations, the PROfound study did show significant benefit of olaparib in BRCA-mutated patients.”

Rucaparib (Rubraca) has a different indication; it is approved for the treatment of patients with deleterious BRCA mutation associated mCRPC, whether germline and/or somatic, based on findings from the TRITON2 trial.⁴

Although responses were mostly seen with rucaparib in patients with BRCA mutations, additional analyses have explored responses in patients with other HRR mutations tested in the trial (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, and RAD54L).In the analysis, limited responses were observed in patients with ATM, CDK12, and CHEK2 alterations, including a radiographic response rate of 10.5% in the ATM cohort.Responses were also observed in patients with DNA damage repair gene alterations with a radiographic response rate of 28.6%.⁵

Maxwell stated, “the question you want to ask yourself is I have a [patient with] metastatic prostate cancer in front of me, what tests do I want to order that will evaluate these 2 very promising, and both FDA approved, therapies for my patients?”

The FoundationOne CDx is one of the more commonly ordered tests in the Northeast and covers all of the HRR genes included in the FDA approval for olaparib among the 309 genes tested with the assay. The assay also covers microsatellite instability (MSI) testing. Maxwell clarified that the FoundationOne Liquid assay does not cover all of the HRR alterations.

Additional biomarkers for treatment in prostate cancer include biomarkers that relate to tumor-agnostic approvals, including MSI-high disease for use with pembrolizumab (Keytruda) or NTRK gene fusions for use with either larotrectinib (Vitrakvi) or entrectinib (Rozlytrek).

NTRK gene fusions are found infrequently in prostate cancers, with NTRK1 demonstrating a frequency of 3.0% (2 of 67) and NTRK3 of 1.5% (1 of 67) in an analysis of actionable genomic alterations in prostate cancer.⁶ However, when these alterations are found, both TRK inhibitors can be beneficial in this setting.

When pembrolizumab was tested in patients with prostate cancer in the KEYNOTE-199 trial (NCT02787005), responses to treatment were limited; however, this was not a biomarker-based study so it did include all-comer patients with mCRPC. The response rate in KEYNOTE-199 was 3% to 5%.⁷

However, an analysis of a few patients with metastatic prostate cancer and MSI-high disease, as detected by circulating tumor DNA with the Guardant360 assay, showed a higher response rate of 60%, including 1 complete response.⁸ Additionally, about half of the patients had both MSI-high disease and alterations in BRCA1/2.

References:

1. Maxwell KN. Biomarker Review: Predictive/Actionable Biomarkers for Metastatic Prostate Cancer. Presented at: 21st Annual Meeting of the Society of Urologic Oncology; December 2-5, 2020; Virtual.

2. Dan R, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001

3. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440

4. Abida W, Patnaik A, Campbell D, et al; TRITON2 investigators. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. Published online August 14, 2020. doi:10.1200/JCO.20.01035

5. Abida W, Campbell D, Patnaik A, et al. Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study. Clin Cancer Res. 2020;26(11):2487-2496. doi:10.1158/1078-0432.CCR-20-0394

6. Ikeda S, Elkin SK, Tomson BN, Carter JL, Zurzrock R. Next-generation sequencing of prostate cancer: genomic and pathway alterations, potential actionability patterns, and relative rate of use of clinical-grade testing. Cancer Biol Ther. 2019;20(2):219-226. doi:10.1080/15384047.2018.1523849

7. Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol. 2020;38(5):395-405. doi:10.1200/JCO.19.01638

8. Barata P, Agarwal N, Nussenzveig R, et al. Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA. J Immunother Cancer. 2020;8(2):e001065. doi:10.1136/jitc-2020-001065