Integrating Genetic Testing Into Prostate Cancer Guidelines Leads to Improved Treatment Decisions

Updated National Comprehensive Cancer Network (NCCN) guidelines in prostate cancer recommend integration of tumor genetic testing into clinical practice for patients with advanced prostate cancer. For patients with regional or metastatic disease, the guidelines recommend testing for homologous recombination gene mutations and for microsatellite instability (MSI) or mismatch repair deficiency (dMMR), according to Emmanuel S. Antonarakis, MBBCh.

In a presentation during the NCCN 2019 Annual Conference in Orlando, Florida, Antonarakis addressed the role of genetic testing.

The genes detected in patients with prostate cancer fall into 2 classes: mismatch repair (MMR) and homologous recombination deficiency (HRD). In an interview with Targeted Therapies in Oncology, Antonarakis, associate professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland, discussed the prevalence of these different genes.

Two main types of genetic testing, germline or somatic, need to be considered, Antonarakis said.

The updates recommend germline testing for every patient with metastatic prostate cancer and high-risk, localized nonmetastatic disease. Men with very low-risk prostate cancer are excluded from the new guidelines, Antonarakis said. What about somatic testing? “The guidelines say that anyone who has lymph node metastases should also undergo tumor somatic testing,” he said.

This leads to questions regarding the genes’ prevalence in prostate cancer and what can be done with this information. The most informative type of gene mutations to the oncologist involve 2 classes of genes, MMR and HRD.

MMR genes are responsible for Lynch syndrome. These genes—MSH2, MSH6, MLH1, and PMS2—are responsible for hypermutated tumors.

The MMR mutation is seen in only about 3% to 5% of all advanced prostate cancers, but the guidelines recommend pembrolizumab (Keytruda) in patients with this mutation.

The second class of mutations, HRD genes, include BRCA2, BRCA1, ATM, and a number of others. “Collectively, these gene mutations make up between 20% and 25% of all advanced prostate cancers. Even though testing for these HRD genes is recommended, we do not currently have any FDA-approved therapies specifically targeting those patients,” Antonarakis said. “There is a lot of interest in using PARP inhibitors like olaparib (Lynparza) or rucaparib (Rubraca) for those patients.”

Clinical trials are exploring the use of these agents in patients with an HRD gene. For referral to a PARP inhibitor trial, a patient must first be found to have an HRD mutation, such as BRCA2. “The guidelines do not endorse the off-label use of a PARP inhibitor for a patient with an HRD-positive prostate cancer,” Antonarakis said.

Studies involving pembrolizumab in patients with dMMR include a phase II study evaluating the clinical activity of pembrolizumab in 41 patients with progressive metastatic carcinoma, with or without dMMR. An objective response rate (ORR) and immune-related progression-free survival rate of 40% (4 of 10 patients) and 78% (7 of 9 patients) were observed, respectively.¹

Similarly, a phase II study of 86 patients evaluated the efficacy of PD-1 blockade in patients with advanced dMMR cancers across 12 tumor types.²Investigators reported objective radiographic responses in 53% of patients, with 21% achieving complete radiographic response.

“Those studies showed that for the first time, irrespective of what type of cancer you have— whether it’s colorectal cancer, prostate cancer, or breast cancer—if you have an MMR mutation, you have an extremely high chance of responding to pembrolizumab,” he said.

In prostate cancer, KEYNOTE-1993 investigated pembrolizumab in 258 patients with metastatic castration-resistant prostate cancer. In that study, the ORR for single-agent pembrolizumab was around 4% to 5%, Antonarakis said.

PARP Inhibitors

One of the most exciting things in the management of prostate cancer is the investigational use of PARP inhibitors. These agents have been approved by the FDA for a few cancer types, but not for prostate cancer. Olaparib and rucaparib are being studied in the phase III setting.

“We are beginning to learn that it does not seem to be enough to have a mutation in 1 of the HRD genes. In fact, the actual gene that is mutated seems to matter,” Antonarakis said. “There are some mutated genes, such as BRCA2, in which the chance of responding to olaparib or rucaparib is quite high—in the 50% to 70% range.

Another relatively common gene is called CHEK2. It was hypothesized that patients with CHEK2 mutations might respond to PARP inhibitors in the context of prostate cancer, but response rates actually were quite low. “The emerging data are pointing to the fact that a patient with BRCA1/ BRCA2-mutated prostate cancer will probably have a very good chance of response to a PARP inhibitor—maybe 50% to 70% chance—but perhaps some of the other genes, like ATM, CHEK2, and other more rare ones, may not respond as well.”

How well a patient with a germline mutation versus a somatic mutation responds to a particular treatment is still unclear, Antonarakis said.

“What we don’t yet know is whether, for example, a germline BRCA2 mutation will have a higher response to a PARP inhibitor in prostate cancer compared with a somatic-only mutation. Not only does the gene itself matter but also whether the germline tumor DNA may be an additional factor that might predict sensitivity or perhaps resistance to PARP inhibitors,” he said.

Antonarakis emphasized that genetic tests are commercially available, approved by the FDA, and reimbursed by insurance companies, so physicians should not be hesitant to order them. If one of these genes is found to be mutated in the tumor, a saliva or blood sample should be obtained to determine whether this mutation was inherited or not; this can have profound implications for the patient’s first-degree relatives.

“If you begin by doing tumor sequencing and find a BRCA2 mutation, it is paramount to determine if that BRCA2 mutation was inherited or not. If it was inherited, that patient’s family should be counseled about their risk of developing other cancers,” Antonarakis concluded.

References:

1. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015;372(26):2509-2520. doi: 10.1056/NEJMoa1500596.
2. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017;357(6349):409- 413.
3. DeBono JS, Goh JCH, Ojamaa K, et al. KEYNOTE-199: pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).J Clin Oncol. 2018;36(suppl 15):5007. doi: 10.1200/JCO.2018.36.15_suppl.5007.
4. Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade.JAMA Oncol. 2019;5(4):471-478. doi: 10.1001/jamaoncol.2018.5801.