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Advances have been made in prostate cancer screening, detection, assessment of risk, treatment, and follow-up. Gene-based biomarkers and PET/CT imaging show great promise in improving prostate cancer risk assessment and staging, respectively. Hundreds of ongoing clinical trials are exploring novel therapeutic strategies and investigational agents. Today’s update reviews some of these key advances.
Active Surveillance for Low-Risk Prostate Cancer is a Standard of Care and is Here to Stay
Long-term follow-up has demonstrated that active surveillance — rigorous monitoring and careful follow-up — is a safe and effective strategy for appropriately selected men with very low-risk and low-risk prostate cancer. It avoids the morbidity of active treatment and if progression does occur (which only happens very rarely), the delay in treatment does not compromise outcomes. Since Gleason 6 prostate cancer pathologically appears like a cancer under the microscope but clinically does not behave like a cancer (cancers tend to invade and destroy adjacent structures and spread to different sites) there is a lot of hubbub about renaming Gleason 6 without using the word cancer. This remains a controversial and contentious issue, but alternative terms being bandied about are “IDLE” (indolent lesion of epithelial origin) and “INERRT” (indolent neoplasm rarely requiring treatment).
PSMA PET/CT (Prostate specific membrane antigen Positron Emission Tomography/Computerized Tomography)
Prostate specific membrane antigen (PSMA) is a protein found on the surface of prostate cells, whether they are normal or cancerous. This protein is over-expressed in prostate cancer tissue at all stages. PSMA expression is usually low with benign prostate enlargement, increased with prostate cancer, and markedly increased with aggressive prostate cancer, castrate resistant prostate cancer, and metastatic prostate cancer. PSMA PET/CT uses small molecules that bind to prostate specific membrane antigen to enable improved staging and accurate detection of metastases in patients with advanced prostate cancer. Because of its high sensitivity and specificity, it is one of the most promising of the PET radio-pharmaceuticals and is now available for our patients at Summit Health in the Florham Park location.
PSMA-Targeted Therapy for Advanced Prostate Cancer
177Lutetium-PSMA-617 (Lu-PSMA; trade name Pluvitco) was just approved by the FDA for patients with metastatic castrate-resistant prostate cancer who have a positive PSMA PET scan and have been already treated with androgen receptor pathway targeting agents and taxane-based chemotherapy. It delivers a small dose of radiation to prostate cancer cells that may be located anywhere in the body. One part of the molecule recognizes and binds to PSMA and the other part of the molecule delivers the radioactive drug that kills the prostate cancer cell. The drug has been found to prolong quantity and quality of life and reduce prostate cancer progression. Side effects include dry mouth and nausea.
Prostate Biopsy Approach
Although ultrasound-guided trans-rectal prostate biopsy is the most common means of obtaining prostate tissue for pathological examination, trans-perineal prostate biopsy is being increasingly adopted. The trans-perineal approach biopsies the prostate gland via the perineum, the anatomy located between the scrotum and the anus. The advantage of a perineal approach over a rectal approach is a reduction in infection and improved sampling of certain regions of the prostate. Disadvantages of this approach are the need for a template, greater time commitment, and more bleeding because of the increased number of biopsies.
Prostate Biopsy Modification
“Peri-lesion” biopsies are biopsies of tissue adjacent to an area targeted as abnormal on MRI (magnetic resonance imaging). These biopsies increase the detection of prostate cancer.
Prostate Cancer Genetics and Genomics
Our understanding of “germline” mutations (inherited DNA mutations) as an important predisposing cause of aggressive prostate cancer has increased dramatically. 10% of prostate cancers are due to an inherited germline mutation. This is as opposed to “somatic” mutations that occur after birth and are not passed on to children. 90% of prostate cancer is due to non-inherited, acquired somatic mutations
The most common mutations found in prostate cancer are the BRCA2 (BReast CAncer gene) mutation, which accounts for about 50% of hereditary prostate cancer mutations, and Lynch syndrome mutation. BRCA1 mutations double the risk of metastatic castrate-resistant prostate cancer (prostate cancer that has spread and is resistant to treatments that decrease testosterone). BRCA2 mutations increase the risk of metastatic castrate resistant prostate cancer by a factor of 4-6, with earlier onset, higher grade at diagnosis and shorter survival. More than 20% of men with metastatic castrate resistant prostate cancers are found to have germline mutations, most commonly BRCA2. Lynch syndrome (hereditary non-polyposis colorectal cancer) is an inherited cancer syndrome causing mutations in DNA repair genes called MMR genes (MisMatch Repair). Because of this predisposition to mutation resulting from impaired DNA repair, those with Lynch syndrome have increased risk not only of colorectal cancers, but a host of other cancers including prostate cancer.
Whereas germline mutation assessment (genetic testing) helps assess one’s risk for prostate cancer, genomic testing examines the genes in a prostate cancer specimen and helps with decisions regarding treatment. Genomic testing can help predict how aggressively a prostate cancer might behave and how likely it is to advance and metastasize.
Our urology group–New Jersey Urology— uses Myriad’s multigene panel for germline testing to determine the presence of 10 genetic mutations commonly implicated in inherited prostate cancer. Specimens are obtained either through a saliva or blood sample and results are typically available in 2-3 weeks. This panel includes the following genes: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, TP53, NBN, and HOXB13.
Prostate Cancer Precision Medicine
Genetic testing has given rise to the exciting field of precision medicine, individualized and customized treatment strategies with medications targeted against specific mutations, a treatment based upon cancer biology and no longer only cancer histology. For example, in patients with BRCA mutations there is a significant improvement in survival using PARP (poly ADP ribose polymerase) – inhibitors.
Radiation Therapy for Prostate Cancer Spread to Pelvic Lymph Nodes
Several recent studies have demonstrated the potential benefits of radiation therapy to the pelvic region when prostate cancer has metastasized to the pelvic lymph nodes.
Androgen Deprivation Therapy in Pill Formulation
In December 2020, the FDA approved Orgovyx, the first once-a-day pill for the treatment of adults with advanced prostate cancer. Orgovyx is dosed at three 120 mg tablets the first day and 120 mg daily thereafter. Castrate levels of testosterone are achieved within one week and are thereafter sustained.
Benefits include once daily oral dosing (versus the conventional injections), rapid testosterone suppression within days (versus much slower with many of the injectables), and avoidance of the testosterone surge (flare) seen with many of the injectables. When the medication is discontinued there is a more rapid testosterone recovery versus much slower recovery with the injectables. Finally, there is decreased potential risk for major cardiac events (heart attack and stroke) as compared to many of the injectables.
The most common side effects of Orgovyx are hot flashes, elevated serum glucose, elevated serum triglycerides, musculoskeletal pain, anemia, abnormal liver function tests, constipation, and diarrhea. In a large clinical trial, serious adverse reactions occurred in 12% of patients, including myocardial infarction (0.8%), acute kidney injury (0.6%), arrhythmia (0.6%), hemorrhage (0.6%), and urinary tract infection (0.5%). Fatal and non-fatal myocardial infarction and stroke were reported in 2.7% of patients.
As with many new drugs, cost is a major concern with the pricing set at $2300/monthly with insurance coverage remaining to be seen.
