While the routine clinical use of targeted-next generation sequencing (NGS) to identify targetable genomic alterations in metastatic prostate cancer has increased over the past years, there is still a profound lack of consensus regarding testing standards. In particular, limited data are available regarding the role of genomic instability assays to functionally assess homologous recombination deficiency (HRD) and their use as a predictive biomarker in advanced prostate cancer. Similarly, heterogeneous technical approaches are available for assessing microsatellite instability (MSI-H), including immunohistochemistry, microsatellite polymerase chain reaction (PCR), and NGS. For localized prostate cancer, multigene expression assays or genomic classifiers have been proposed to improve risk stratification and personalize the clinical management of patients with non-metastatic disease. However, despite a long history of research and clinical use, a similar lack of consensus concerns their optimal clinical use.
Thus, in our work, we aimed to provide an overview of the prostate cancer molecular landscape and summarize current evidence regarding molecular tumor and germline testing in localized and advanced prostate cancer.
What is the therapeutic impact of tumor molecular profiling for localized and advanced prostate cancer?
HRD, MSI-H, and CDK12 deficiency constitute the main actionable genomic alterations in advanced prostate cancer. Globally, homologous recombination repair (HRR) and Fanconi Anemia pathway alterations occur in up to 25% of metastatic prostate cancers, with the most frequent alterations reported in BRCA2 and ATM.1,2 Olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), is FDA approved for HRR-altered metastatic castration-resistant prostate cancer (mCRPC), which progressed after treatment with a new hormonal agent, based on the results of the PROfound phase 3 trial.4 Based on tumor responses observed in the TRITON2 phase 2 trial, rucaparib, another PARPi, was also approved for patients with pathogenic somatic or germline BRCA1 or BRCA2 mutations, which progressed to a previous taxane-based chemotherapy.5 The phase 3 TRITON3 trial, investigating the efficacy of rucaparib in chemotherapy-naïve patients, showed progression-free survival (PFS) benefit for patients with BRCA1/2-mutated tumors. The overall survival data from this trial are yet immature. Moreover, recent phase 3 PROPEL and MAGNITUDE trials are investigating the role of olaparib and rucaparib, retrospectively, combined with abiraterone and prednisone as first-line mCRPC treatment. Both trials demonstrated PFS benefit for HRR-altered tumors, which was more relevant for BRCA1/2-mutated tumors.6,7 Similarly, biomarker analysis from the phase 2 TOPARP-B trial showed that olaparib was most effective for specific HRR alterations, in particular, homozygous BRACA2 deletions, PALB2 with biallelic loss, and ATM deficiency on the protein level. Relevantly, responses to PARPis for the rest of HRR alterations were highly variable.8 For these alterations, a complementary assessment with HRD genomic instability assays might clarify the potential benefit of PARPis.
MSI-H or mismatch repair deficiency (dMMR) has been reported in 4-5 % of advanced prostate cancers and is less frequent in localized stages (1%). Similarly to other MSI-H/dMMR cancers, these tumors show vulnerability to immune checkpoint inhibitors (ICIs). Pembrolizumab is FDA approved for unresectable or metastatic MSI-H/dMMR solid tumors, including prostate cancer, which progressed to a previous systemic treatment line. Pembrolizumab is also approved and may be considered for advanced solid tumors with a high tumor mutational burden (TMB) of >/= 10 mutations/megabase.
CDK12 inactivating alterations occur in up to 5% of prostate cancers. These tumors are characterized by aggressive clinical course and show variable sensitivity to ICIs.9
For localized prostate cancer, molecular profiling with targeted DNA NGS is not recommended. However, the use of gene expression panels, such as Decipher, combined with clinical and radiographical criteria, may help identify patients with biologically more aggressive disease. In particular, for patients who experience biochemical recurrence after radical prostatectomy and will receive salvage radiotherapy, a higher genomic classifier score may predict a greater benefit from the addition of androgen deprivation therapy.10
What are other clinical implications derived from tumor molecular testing?
Previous studies have shown that the presence of DNA repair alterations in prostate cancer is correlated with a high probability of germline alterations, particularly for BRCA1, BRCA2, CHEK2, PALB2, and ATM, as well as for dMMR-related genes. Another gene associated with high germline probability is HOXB13.11 Thus, germline testing should be mainly offered to patients with tumors harboring these alterations. Moreover, germline testing is currently recommended for patients meeting family cancer history criteria and should also be evaluated for all patients with advanced prostate cancer.12 Genetic counseling should be offered to patients with a finding of a pathogenic or likely pathogenic germline mutation.
Written by: Dilara Akhoundova, Felix Y. Feng, Colin C. Pritchard, Mark A. Rubin
Department for BioMedical Research, University of Bern, Bern, Switzerland; Department of Medical Oncology, Inselspital, University Hospital of Bern, Bern, Switzerland., Department of Radiation Oncology, University of California, San Francisco, CA USA., Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Department for BioMedical Research, University of Bern, Bern, Switzerland; Bern Center for Precision Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland.
References:
- Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215-1228 (2015). https://doi.org:10.1016/j.cell.2015.05.001
- Abida, W. et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proceedings of the National Academy of Sciences 116, 11428-11436 (2019). https://doi.org:10.1073/pnas.1902651116
- Tukachinsky, H. et al. Genomic Analysis of Circulating Tumor DNA in 3,334 Patients with Advanced Prostate Cancer Identifies Targetable BRCA Alterations and AR Resistance Mechanisms. Clin Cancer Res 27, 3094-3105 (2021). https://doi.org:10.1158/1078-0432.Ccr-20-4805
- de Bono, J. et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. New England Journal of Medicine 382, 2091-2102 (2020). https://doi.org:10.1056/NEJMoa1911440
- Abida, W. et al. Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. Journal of Clinical Oncology 38, 3763-3772 (2020). https://doi.org:10.1200/JCO.20.01035
- Saad, F. et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Journal of Clinical Oncology 40, 11-11 (2022). https://doi.org:10.1200/JCO.2022.40.6_suppl.011
- Chi, K. N. et al. Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. Journal of Clinical Oncology 40, 12-12 (2022). https://doi.org:10.1200/JCO.2022.40.6_suppl.012
- Carreira, S. et al. Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Cancer Discovery 11, 2812-2827 (2021). https://doi.org:10.1158/2159-8290.Cd-21-0007
- Antonarakis, E. S. et al. CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors. JCO Precision Oncology, 370-381 (2020). https://doi.org:10.1200/po.19.00399
- Akhoundova, D., Feng, F. Y., Pritchard, C. C. & Rubin, M. A. Molecular Genetics of Prostate Cancer and Role of Genomic Testing. Surg Pathol Clin 15, 617-628 (2022). https://doi.org:10.1016/j.path.2022.08.002
- Truong, H. et al. Gene-based Confirmatory Germline Testing Following Tumor-only Sequencing of Prostate Cancer. Eur Urol (2022). https://doi.org:10.1016/j.eururo.2022.08.028
- Schaeffer, E. et al. NCCN Guidelines Insights: Prostate Cancer, Version 1.2021. J Natl Compr Canc Netw 19, 134-143 (2021). https://doi.org:10.6004/jnccn.2021.0008