Germline testing at diagnosis, along with tumor testing, have the potential to identify candidates for investigational poly (ADP-ribose) polymerase (PARP) inhibitors, and updated guidelines call for their expanded use.
A March 6, 2019, update of the National Comprehensive Cancer Center (NCCN) guidelines for treatment of prostate cancer includes an emphasis on gathering family history and “more careful interrogation of germline mutations,” according to James D. Mohler, MD, associate director and senior vice president, translational research, at Roswell Park Comprehensive Cancer Center.
On Friday, Mohler gave an overview of the guideline updates and Emmanuel S. Antonarakis, MBB.Ch., associate professor of oncology and urology, Sidney Kimmel Cancer Center, John Hopkins School of Medicine, discussed ways to integrate genetic testing into clinical practice at the 2019 NCCN annual conference in Orlando, Florida.
As Mohler discussed, knowledge of the importance of family history in prostate cancer has increased since the 1990s; recent research has shown the importance of germline DNA repair abnormalities, notably BRCA mutations and Lynch syndrome. The mutations can manifest in a host of cancers, including breast, ovarian or pancreatic (NCCN guideline updates in this disease also reflect knowledge gained about germline testing).
More testing recommended. The guidelines update calls for taking a family history immediately at diagnosis; along with prior recommendations to explore BRCA mutations and Lynch syndrome, there is a new recommendation to test for the presence of intraductal carcinoma (IDC). Mohler cited work by Antonarakis that shows this is associated with aggressive disease. If there is a family history of mutations or IDC, germline testing is recommended, preferably with genetic counseling. If family history is unknown, testing may still be considered, based on clinical features.
The guidelines contain a risk stratification and staging workup for germline testing clinically localized disease. Mohler said clinicians can weigh next-generation sequencing (NGS) or targeted testing; if NGS is used, the panel must include BRCA1, BRCA2, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2. The cost of NGS is around $3500, and targeted testing is cheaper, he said.
“By using targeted testing, you could miss mutations that could affect the course of treatment later,” he said. Mohler addressed the controversy over more widespread testing, noting that earlier this year when the American Society of Breast Surgeons called for testing every diagnosed breast cancer patient with a multigene panel. “This is an area where we will have to pay close attention,” he said.
Tumor testing. During his presentation, Antonarakis discussed updates that related to testing of the tumor itself; testing for microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) could inform clinicians whether pembrolizumab is indicated as a second-line or third-line therapy for adenocarcinoma in castration-resistant prostate cancer (CRPC), with or without visceral metastases. “The evidence is level 2B because there is no prospective data, yet we have an FDA approval,” Antonarakis said, referring to the historic approval that pembrolizumab received for a “site agnostic” approval. MMR mutations occur in 3% to 5% of mCRPC patients, he said. The guidelines also call for genetic counseling and germline testing for homologous recombination deficiency (HRD), which Antonarakis said occurs in 15% to 25% of mCRPC cases. Where HRD is found, investigational poly ADP ribose polymerase (PARP) inhibitors can be considered, he said.
Patients with intermediate risk. The group of patients classified as “intermediate” risk is large and diverse, representing a challenge for clinicians developing treatment approaches. Patients in this group are divided into favorable and unfavorable groups; the new guidelines say that for the favorable group, after initial therapy, observation is now preferred; for the unfavorable group, the following apply: initial therapy is changed from external beam radiation therapy (EBRT) + ADT for 4-6 months to EBRT ± androgen deprivation therapy (ADT) for 4-6 months; or initial therapy is changed to EBRT + brachytherapy ± ADT for 4-6 months.
Mohler drilled down into data comparing using ADT intermittently and continuously; new language calls for considering intermittent ADT in M0 PSA cancer. He noted language now appearing in the guidelines: “Whether treatment of regional nodes in addition to the primary improves outcomes remains uncertain; nodal treatment should be performed in the context of a clinical trial.”
For metastatic castration-naive disease, “ADT is the gold standard,” the guideline reads, but a phase 3 trial comparing continuous with intermittent could not show non-inferiority for survival. Quality of life was better in the intermittent arm.
Castration-Resistant Prostate Cancer (CRPC). Updates also addressed secondary hormone therapy in non-metastatic CRPC, or M0 CRPC. He reviewed clinical trials that led to recommendations for apalutamide and enzalutamide, which appear in the guidelines as well as a trial for darolutamide, which is not yet approved and “thus is not included in the guidelines.”
Mohler said there had been a “rousing debate” whether these therapies should become the new standard of care. And then he addressed the cost of the therapies. If a man is diagnosed with CRPC that becomes metastatic, the cost of therapy an easily run from $500,000 to $1 million.
“We need to start thinking about the cost of treatment or [financial] toxicity,” which he said is becoming a bigger problem for families of prostate cancer patients, more so than other common cancers “We need good data in this field, and there’s not a whole lot.”