Prostate Cancer Treatment
Novel and Emerging Strategies
Improvements to Conventional Treatments
Commonly used treatments such as radical prostatectomy, radiation, and hormone therapy are constantly being reviewed and refined to improve patient survival and quality of life (NCCN 2017b). For example, identifying patient groups that are most likely to benefit from specific treatments is an active area of research. Recent clinical data suggest radical prostatectomy might be helpful even for men with advanced or high-risk disease (Weiner 2017; Gandaglia 2017; O'Shaughnessy 2017). Surgery may be particularly effective in this patient group when used in conjunction with radiation therapy (Fahmy 2017; NCCN 2017b).
Researchers are also developing new evidence regarding the optimal order and combinations of various treatments. As described earlier, docetaxel may be more effective when used before resistance to testosterone-lowering therapy develops (Estevez 2016). Other research is addressing issues such as which hormone therapy should be used first and when it should be started (Moul 2015; Dijkstra 2016; Ho 2017; Chu 2015).
Finally, new medications for treating prostate cancer are being studied. A newer second generation of hormone therapies is in development (Wadosky 2016; Bambury 2016; Petrunak 2017). Seviteronel, also known as VT-464, is an androgen synthesis inhibitor that is undergoing fast-track review by the FDA for approval in patients with metastatic castration-resistant disease (Norris 2017; Teply 2016; Pharmacutical Technology 2017). Apalutamide is a new androgen receptor blocker granted priority review by the FDA in late 2017 based on promising results from the phase-III SPARTAN trial. The priority review is for use in men with nonmetastatic castration-resistant prostate cancer; the FDA’s opinion is expected by April, 2018 (Smith 2016; Broderick 2017).
High-Intensity Focused Ultrasound
High-intensity focused ultrasound (HIFU) is being tested in men with newly diagnosed prostate cancer and those with cancer recurrence after radiation (NCCN 2017b; Golbari 2017; Garcia-Barreras 2017; Crouzet 2017). In this approach, ultrasound is focused on the tumor and its concentrated energy destroys the targeted tumor cells (NCCN 2016b; NCI 2018b; Kim 2008; Malietzis 2013).
HIFU is currently approved by the FDA for prostate tissue ablation, but is not specifically approved as a treatment for prostate cancer (Nelson 2015). HIFU may cause fewer side effects than radical prostatectomy, and initial studies suggest it may be equally effective in low-risk patients; however, more research is needed (Garcia-Barreras 2017; Kanthabalan 2017; Jones 2017; Albisinni 2017).
Vascular-Targeted Photodynamic Therapy
Vascular-targeted photodynamic therapy involves injection of a photosensitizing, or light-sensitizing, drug. Small laser fibers are inserted into the prostate to activate the drug locally, and the activated drug destroys blood vessels supporting the tumor (NCCN 2016b).
A phase-III clinical trial evaluated vascular-targeted photodynamic therapy in men with low-risk prostate cancer. Side effects were rare, and fewer men in the photodynamic therapy group (about 30%) than the active surveillance group (about 60%) had disease progression after two years (Azzouzi 2017). Moreover, almost half of the patients that underwent photodynamic therapy, compared with only 14% in the active surveillance group, had a cancer-free biopsy sample two years after treatment (Stone 2017).
Targeted therapies are designed to block or inhibit specific molecules that help cancer grow. Olaparib (Lynparza) is a type of drug that interferes with a protein called poly ADP ribose polymerase, or PARP, that helps cancer cells repair their DNA (NCCN 2017b). Olaparib and other PARP inhibitors may be effective treatments for men with tumors that rely on this DNA repair function (Ramakrishnan Geethakumari 2017).
In a phase-II clinical trial, 88% of patients with defects in tumor DNA-repair genes responded to olaparib (Mateo 2015). Researchers are developing tests to identify patients who are likely to respond to olaparib and other targeted drugs (Goodall 2017). In 2016, the FDA granted olaparib “breakthrough therapy” designation for metastatic castration-resistant prostate cancer, which ensures its rapid review (Ramakrishnan Geethakumari 2017; Helleday 2016).
Another emerging therapy targets prostate-specific membrane antigen, or PSMA, which is highly concentrated on the surface of prostate cancer cells. Agents called PSMA ligands bind PSMA and carry a radioactive substance to destroy the prostate cancer cells (Eiber 2017; Kulkarni 2016).
In a recent study, 145 patients with advanced prostate cancer were treated with a PSMA ligand. Forty-five percent had reductions of at least 50% in their PSA levels (Rahbar 2017). Two other studies found PSA levels decreased in about 80–90% of patients after treatment with PSMA-directed radiotherapy (Baum 2016; Brauer 2017).
Immunotherapy, an approach that uses the patient’s own immune system to fight cancer, was named the “cancer advance of the year” by the American Society of Clinical Oncology in both 2016 and 2017 (Madan, Gulley 2017; Rijnders 2017; Burstein 2017; Dizon 2016). Sipuleucel-T was one of the first FDA-approved immunotherapies (Madan, Gulley 2017).
Cancer vaccines deliver a cancer-specific protein to the body and direct the immune system to target cells that contain that protein (Sayour 2017). A vaccine developed for prostate cancer called PROSTVAC was designed to trigger the immune system to attack cells that have PSA on their surface (Mandl 2014; DiPaola 2015). Phase I – II clinical trials of PROSTVAC in combination with other anti-cancer agent, are ongoing as of early 2018. Results of these trials will help establish the utility of PROSTVAC for treating prostate cancer (Madan 2017; Fong 2017; Gulley 2017). Several other vaccine approaches are also currently being tested in earlier stage clinical trials (Lilleby 2017; Heery 2016; Yoshimura 2016).
Checkpoint inhibitors are another class of immunotherapy agents. These drugs were developed in response to the discovery of immune checkpoint proteins, which tumor cells engage to deactivate immune cells (Azoury 2015; Dyck 2017). Checkpoint inhibitors interfere with this process, allowing the patient’s immune system to continue fighting the tumor (Rijnders 2017; Madan, Gulley 2017; Popovic 2017). In a small study testing the checkpoint inhibitor pembrolizumab (Keytruda) in patients with metastatic castration-resistant prostate cancer, three of 10 patients experienced rapid and dramatic PSA level reductions (Graff 2016). Similarly remarkable responses to the checkpoint inhibitors nivolumab (Opdivo) and ipilimumab (Yervoy) have been described in case reports (Basnet 2017; Cabel 2017). Additional clinical trials will help determine which patients are most likely to benefit from checkpoint-inhibitor immunotherapy (Popovic 2017).
Chimeric antigen receptor (CAR)-modified T-cell immunotherapy involves taking the patient’s T cells, genetically engineering the T cells to produce receptors that direct them to the cancer cells, and returning these CAR T cells to the patient’s body (NCI 2017b). In a phase-I clinical trial, 50% and 70% reductions in PSA levels were seen in two of five patients treated with CAR T-cell therapy (Junghans 2016). Promising results from animal models of prostate cancer using CAR T-cell therapy provide a foundation for further investigation (Kloss 2013; Gade 2005; Ma 2014; Zuccolotto 2014).
More information is available in the Cancer Immunotherapy protocol.
Screening, Diagnostic, and Prognostic Tests
Many men with slightly or moderately high PSA levels do not have cancer detected in their biopsy or do not have an aggressive form that needs treatment (Thompson 2004; Saini 2016). Several new tests are being developed to help men with moderate PSA level elevations decide whether to have a biopsy (Dani 2017; Carlsson 2017). A composite test called 4Kscore uses measurements of four different proteins in the blood along with clinical information about the patient to predict the likelihood that the cancer will spread within the next 15–20 years (Punnen 2015; Zappala 2017; Stattin 2015). A meta-analysis of published data concluded that the diagnostic accuracy of this test is similar to that of the FDA-approved Prostate Health Index (Russo 2017).
Genetic markers from cells in urine collected after a digital rectal exam may be useful predictors of cancer aggressiveness (Martignano 2017). In a trial with 1,077 participants, combined measurement of the gene markers TMPRSS2:ERG and PCA3 improved the ability to identify men at low risk for aggressive disease compared with PSA testing alone (Sanda 2017). Researchers examining genetic markers in urine samples from 905 participants with prostate cancer found two other markers (HOXC6 and DLX1 mRNA levels) that could help identify those with high-grade cancer (Van Neste 2016). These genetic tests could someday play a role in avoiding unnecessary biopsies (Martignano 2017).
New tests are also being developed to analyze tissue obtained through biopsy. The tissue may look healthy under a microscope, but certain molecular changes could indicate that a nearby cancer was missed by the biopsy needles. ConfirmMdx (Stewart 2013; Partin 2016) and the Prostate Core Mitomic Test (PCMT) (Robinson 2010; Legisi 2016) are two examples of commercially available tissue tests. Patients testing negative with these tests may opt for fewer or less frequent repeat biopsies (Wojno 2014; Legisi 2016).
Prostate tissue obtained through biopsy or surgery can be analyzed with new tests that may provide information on how aggressively the cancer should be treated:
- Decipher has been assessed in over 2,000 patients and may predict the risk of metastasis (Nguyen 2017; Spratt 2017).
- Oncotype DX Prostate Cancer Assay may provide information on tumor aggressiveness for men with clinically low-risk disease facing the choice between active surveillance or treatment (Brand 2016).
- Prolaris and Promark may help prevent overtreatment by identifying men who are unlikely to benefit from more aggressive treatment (Cuzick 2015; Tosoian, Chappidi 2017; Koch 2016; Blume-Jensen 2015; Peabody 2017).
Although these tests are available and covered by Medicare for eligible patients, long-term and randomized trials are needed to confirm and compare their value (McMahon 2017; Metmark Genetics 2016).
Developments in imaging may improve diagnosis and assessment of prognosis. Positron emission tomography, or PET, provides information on how tissues and organs are functioning by measuring processes such as glucose metabolism and blood flow. PET scans use molecules called tracers that associate with cancers (Bednarova 2017). Researchers are working to understand how results from PET scans using various tracers can inform and improve treatment decisions (Dietlein 2017; Nanni 2016).
Repurposing Existing Drugs
Some drugs that are approved for the treatment of other diseases may be useful for treating prostate cancer. Much of the evidence supporting the potential benefits of these drugs comes from observational rather than clinical trials; however, several controlled trials are either underway or are being planned. The completion of such trials will help clarify whether there is a role for these repurposed drugs in prostate cancer treatment.
Statins are a category of cholesterol-lowering drugs. Among men with prostate cancer, those with high cholesterol levels are more likely to have high-grade and metastatic prostate cancer (Schnoeller 2017; Thysell 2010). In addition, men using statins to manage cholesterol have a lower risk of advanced prostate cancer and higher rate of prostate cancer survival (Alfaqih 2017). Several mechanisms by which statins may combat prostate cancer have been proposed, including modulation of cholesterol-signaling pathways in prostate tumors (cholesterol is the precursor to androgens, so statins may reduce androgen bioavailability in prostate cancer cells). Statins may also influence enzymes that participate in cell migration and tumor progression. Randomized controlled trials are needed to determine whether adding statins to prostate cancer treatment leads to better outcomes (Mucci 2017).
Preliminary data suggest aspirin may reduce prostate cancer recurrence (Smith 2017), prostate cancer-related death (Jacobs 2014), or death from any cause (Zhou 2017). The ADD-ASPIRIN trial is recruiting over 2,000 patients with prostate cancer to further test whether aspirin can prevent cancer recurrence (Coyle 2016).
The diabetes drug metformin may slow prostate cancer growth (Whitburn 2017; Sarmento-Cabral 2017). Metformin has been shown to enhance the ability of hormone therapy and radiation therapy to destroy prostate cancer cells in the lab and prostate tumors in mice (Colquhoun 2012; Whitburn 2017; Zhang 2014; Liu 2017). In one study in 44 men with metastatic prostate cancer, metformin (1,000 mg twice daily) stabilized the disease and extended PSA doubling time in a significant number of participants (Rothermundt 2014).