As the Nobel Laureate Bob Dylan wrote, “The times they are a-changin’.” Heather Cheng, MD, PhD, Associate Professor, University of Washington, Associate Member, Fred Hutchinson Cancer Research Center, and Director, Seattle Cancer Care Alliance, Prostate Cancer Genetics Clinic, quoted this line in regard to biomarkers for molecularly driven therapy for prostate and other genitourinary cancers, emphasizing the progress that has been made, during her presentation at the 2019 Annual Chemotherapy Foundation Symposium.1
Heather Cheng, MD, PhD
As recently as 2005, no biomarkers for treatment response had been identified for prostate cancers (or other genitourinary malignancies), and the field has lagged behind breast and lung cancers in this regard. However, in 2019, molecularly driven therapies are available for kidney, bladder, and prostate cancers, including some with biomarkers for treatment response.
Dr. Cheng focused most of her remarks on prostate cancer, although she mentioned that both advanced kidney cancer and advanced urothelial cancer now have validated molecular targets. For advanced kidney cancer, vascular endothelial growth factor receptor (VEGFR), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and programmed cell death ligand 1 (PD-L1) are targetable with axitinib, ipilimumab, and nivolumab, respectively, as well as axitinib in combination with avelumab or pembrolizumab. For urothelial and bladder cancers, targets/alterations include programmed cell death protein 1 (PD-1)/PD-L1, fibroblast growth factor receptor 2 (FGFR2), and FGFR3. Five immune checkpoint inhibitors that target PD-1 and PD-L1 are available without individual patient selection by PD-L1 expression: atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab. Erdafitinib is now available for patients whose urothelial cancers have evidence of FGFR2 and FGFR3 alterations.
“Published data show that PD-L1 expression is inconsistent as a biomarker for checkpoint inhibitor therapy in urothelial and bladder cancers, and more study is needed. Other markers are also being explored, including tumor -mutational burden, DNA damage repair genes, and gene-expression signatures,” she continued.
“Erdafitinib is the ‘new kid on the block’—a new biomarker-selected option for patients with advanced urothelial cancers,” stated Dr. Cheng. This agent targets FGFR alterations, which occur in an estimated 15% to 20% of metastatic urothelial cancers. Recently, the U.S. Food and Drug Administration (FDA) approved erdafitinib for FGFR2- or FGFR3-mutated locally advanced and metastatic urothelial cancers; this approval was based on phase II data showing an objective response rate of 40% and a median progression-free survival of 5.5 months. In addition, there is an approved companion diagnostic to be used in this indication.
Molecular Landscape of Metastatic Prostate Cancer
EARLY Evidence of molecular targets in prostate cancer came from a study of 150 biopsies of metastatic castration-resistant prostate cancer; it showed that about 25% of these patients had defects in DNA repair genes, most commonly BRCA2, ATM, BRCA1, MSH2, and MSH6.2 Eight percent of the DNA repair defects were identified as germline (inherited) defects.
A practice-changing study of patients with metastatic prostate cancer found that more than 10% had inherited DNA repair defects found in germline mutations, irrespective of family history or age of disease onset.3 Another study showed that based on guidelines for genetic testing at the time (historically based on family history of cancers), 40% of patients with inherited cancer risk would not have been offered testing.4
The 25% of patients with castration-resistant prostate cancer who have DNA repair defects in tumors (found by tumor/somatic genetic testing) may be candidates for platinum chemotherapy and may be eligible for ongoing clinical trials of poly (ADP-ribose) polymerase (PARP) inhibitors, she said. “These findings changed our understanding of the landscape of mutations in metastatic castration-resistant prostate cancer and are changing the standard of care for genetic testing. Germline mutations have important implications not only for the patients we see, but may have life-saving implications for their blood relatives. Germline genetic testing is another approach to identifying patients who may be candidates for PARP inhibitor therapy and platinum chemotherapy,” Dr. Cheng told the audience.
Published data show that PD-L1 expression is inconsistent as a biomarker for checkpoint inhibitor therapy in urothelial and bladder cancers.— Heather Cheng, MD, PhD
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Microsatellite instability–high (MSI-high) and mismatch repair–-deficient (MRD) tumors are found in 5% to 10% of patients with metastatic castration-resistant prostate cancer. The immune checkpoint inhibitor pembrolizumab is approved by the FDA in the treatment of solid tumors that harbor these markers, making it “the first tumor-agnostic, molecularly driven approval,” noted Dr. Cheng.
Data are accumulating about the benefits of PARP inhibitor activity in metastatic castration-resistant prostate cancer with defects in homologous recombination DNA repair. An earlier study found an 88% response rate to the PARP inhibitor olaparib in 16 patients with metastatic castration-resistant prostate cancer and evidence of DNA repair defects.5
More recently, the results of the phase III PROfound study were reported at the European Society for Medical Oncology (ESMO) Congress 20196 and in the November 10, 2019, issue of The ASCO Post. Patients were selected by tumor sequencing and enrolled in two different cohorts. The results were presented for cohort A, which included patients whose metastatic castration-resistant prostate tumors had evidence ofBRCA1, BRCA2, and ATM mutations. They were treated with olaparib vs physician’s choice of therapy.
At 12 months, 28% of patients in the olaparib arm were free of blinded independent radiographic disease progression vs 9.4% in the physician’s choice arm. The median radiographic progression-free survival was doubled in the olaparib arm (7.39 months vs 3.55 months, respectively [hazard ratio = 0.34, 95% confidence interval = 0.25–0.47; P < .0001]).
“We anticipate that results of the PROfound trial will lead to FDA approval of olaparib for patients with metastatic castration-resistant prostate cancers whose tumors have mutations in BRCA2, BRCA1, and ATM,” Dr. Cheng told the audience. “PARP inhibitors have not typically been used to treat prostate cancer. If PARP inhibitor therapy is not available or not covered by insurance, emerging evidence suggests that platinum chemotherapy is an option for these patients as well.”
Changing Standard of Care for Genetic Testing
“These findings are changing the standard for care for genetic testing,” commented Dr. Cheng. “In metastatic castration-resistant prostate cancer, consider molecular tumor testing [ie, somatic testing] for homologous DNA repair gene mutations, MSI, or mismatch repair defects,” she added. The most recent National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend germline testing for all patients with a family history of cancer; ductal or intraductal cancer; high-risk and very high–risk localized disease; and for regional, nodal, and metastatic disease.”
Dr. Cheng believes that the new intersection of germline and somatic testing is transforming clinical practice. “Biomarker selection by tumor vs germline is still being defined,” she continued. “Germline testing alone will miss somatic-only tumors with DNA repair deficiency, but if pathogenic germline mutations are observed incidentally, dedicated, confirmatory germline testing with genetic counseling is critical.”
Dr. Cheng noted that germline testing is more straightforward to perform than tumor testing. “It can be done with saliva or blood,” she commented. “Be sure to discuss the risks and benefits with your patients and to work closely with genetic counseling professionals, especially if germline mutations are found. We have more to learn about which mutations are predictive of treatment response.” ■
DISCLOSURE: Dr. Cheng reported financial relationships with Astellas, Clovis, Color Genomics, Janssen, Medivation, and Sanofi.
2. Robinson D, Van Allen EM, Wu YM, et al: Integrative clinical genomics of advanced prostate cancer. Cell 162:454, 2015.
3. Pritchard CC, Mateo J, Walsh MF, et al: Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 375:443-453, 2016.
4. Nicolosi P, Ledet E, Yang S, et al: Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol 5:523-528, 2019.
5. Mateo J, Carreira S, Sandhu S, et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 373:1697-1708, 2015.
6. Hussain M, Mateo J, Fizazi SK, et al: PROfound: Phase III study of olaparib vs enzalutamide or abiraterone for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations. ESMO Congress 2019. Abstract LBA12_PR. Presented September 30, 2019.