For patients with advanced prostate cancer, hormonal treatment with androgen deprivation therapy (ADT) has been the standard treatment for many decades now. For more details regarding androgen deprivation therapy, please see as separate article. In the last 10 years or so, researchers and doctors have found that adding additional treatments to androgen deprivation therapy can improve outcomes, lengthening how long men live after being diagnosed with prostate cancer and improving their quality of life.

Among the available treatment options, there are two main categories – chemotherapy and targeted therapies. The role of chemotherapy in advanced prostate cancer is discussed in another article; this one will focus on targeted therapies. Currently, there are two categories of targeted therapies that have been approved for men with advanced prostate cancer – those that target the androgens (testosterone) that fuel prostate cancer growth (so-called “novel hormonal agents” [NHAs] or “androgen receptor antagonist treatment” [ARATs]) and those that target how cancer cells recover from DNA damage to keep growing (so-called “PARP inhibitors”).

Novel hormonal agents

Beginning with studies of abiraterone acetate and enzalutamide in men who had very advanced prostate cancer progressing after ADT and chemotherapy, adding novel hormonal agents (including abiraterone acetate, enzalutamide, apalutamide, and darolutamide) to ADT has shown benefit for men with advanced prostate cancer. These treatments are now approved for men who are newly diagnosed with metastatic prostate cancer who are starting ADT for the first time (metastatic hormone sensitive prostate cancer), those who have cancer that is developing resistance to ADT without evidence of metastasis (non-metastatic castration resistant prostate cancer), and those who cancer metastatic cancer that has developed resistance to ADT (metastatic castration resistant prostate cancer).

Currently, guidelines including those from the National Comprehensive Cancer Network (NCCN), American Urological Association (AUA), and others support the use of these medications for men with any of these three advanced prostate cancer states. Further, ongoing research is looking at whether these treatments may be beneficial for men with other, less advanced forms of prostate cancer. 

Abiraterone acetate acts by blocking the ability of the body to produce testosterone, a hormone which (even after the development of castration resistance) is important for prostate cancer cells to survive and grow. By blocking the body’s ability to produce testosterone, it also blocks the production of other steroid hormones so men taking abiraterone need to also take a steroid medication (such a prednisone, prednisolone, or dexamethasone). Apalutamide, enzalutamide, and darolutamide are all different androgen receptor blockers which act to block the signaling pathway prostate cancer cells need to use to translate testosterone into signals for survival and growth.

PARP inhibitors

Some prostate cancer cells have specific genetic defects in how they respond to and repair damage to their DNA. These defects in proteins necessary for repairing DNA (such as BRCA1, BRCA2, and others) make the cells sensitive to medications called PARP inhibitors that further block the DNA repair process in a synergistic way called synthetic lethality. These medications (including olaparib, rucaparib, and others), while only relatively recently approved for men with advanced prostate cancer have been used for many years in patients with breast and ovarian cancer with similar genetic defects.

The requirement for both an underlying genetic defect and the medication together to act before causing cell death means that these agents are relative specific for cancer cells. However, because of their reliance on the combination with genetic defects in a patient’s tumor, these medications do not work for all men with prostate cancer. Instead, PARP inhibitors can only be used in men with mutations in these relevant genes. Thus, many if not all men with advanced prostate cancer should undergo so-called genetic biomarker testing (either of the tumor [somatic testing] or of their blood [germline testing) to see if they have a mutation that will make their tumor sensitive to these medications. How frequently these mutations will be found varies on how advanced the prostate cancer is but generally ranges from 5-10% among men with early prostate cancer up to 20% or more in men with advanced disease.

Currently, these treatments are only approved for men with advanced metastatic prostate cancer that has already been treated with ADT (metastatic castration resistant prostate cancer) as well as novel hormonal therapies and chemotherapy. However, many ongoing studies are looking at whether these treatments may be beneficial for men earlier on in their treatment.

For men with advanced prostate cancer, treatment with ADT alone is no longer accepted as sufficient in most cases. If your prostate cancer has reached these stages, you should speak to your physician about whether novel hormonal treatments, chemotherapy or other targeted therapies (including PARP inhibitors) may be appropriate. You should also think about whether enrolling in a clinical trial may be right for you – these studies test new treatment approaches and may allow you early access to promising treatments that are not yet approved.

Zachary Klaassen, MD, MSc
Urologic Oncologist, Georgia Cancer Center, Augusta University, Augusta, GA, USA