Treatment Intensification in Metastatic Hormone-Sensitive Prostate Cancer

By Zachary Klaassen, MD, MSc

If you’ve been diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC), you have many treatment options. Doctors and researchers at the Advanced Prostate Cancer Consensus Conference held earlier this year in Lugano, Switzerland reviewed the latest clinical trial information and highlighted key points for clinicians.

Metastatic prostate cancer means that prostate cancer has spread outside of the prostate gland to other organs, most commonly the lymph nodes and bones, but also not uncommonlyto the liver and lungs. mHSPC may manifest in two main ways: the cancer is metastatic at the time of diagnosis (“de novo”), or it has recurred after treatment (“metachronous”) for localized disease (typically after radiation or surgical removal of the prostate gland). Patients with mHSPC are started on androgen deprivation therapy (ADT or “hormone therapy”), and see their PSA drop as the tumor shrinks. 

While historically testosterone was reduced (to very low or “castrate” levels) by removing both testicles (termed bilateral simple orchiectomy), today, most men who need ADT receive medications that accomplish this medically, rather than undergoing surgery. There is a complex signaling pathway between parts of the brain, the pituitary gland, and the testicles that leads to testosterone production. This pathway may be disrupted by medications that affect the signals between the brain and pituitary glands – groups of medications called GnRH (LHRH) agonists (i.e., leuprolide) or antagonists (i.e., degarelix). 

Treatment Intensification: Doublet Therapy

Until recently, ADT alone was the mainstay of treatment. Starting in 2015, data from large clinical trials (the GETUG-AFU15, STAMPEDE, and CHAARTED trials) demonstrated that adding chemotherapy (docetaxel) to ADT improved survival in men with mHSPC to nearly 4 years from their initial diagnosis. Shortly thereafter, other trials showed that adding other oral medications such as abiraterone (the STAMPEDE and LATITUDE trials), apalutamide (the TITAN trial), and enzalutamide (the ENZAMET and ARCHES trials) could also significantly prolong life beyond just ADT alone. Furthermore, additional data from the STAMPEDE trial showed that adding radiation therapy to the prostate gland, even in patients with metastatic disease, prolonged survival.  

Currently, doublet treatment intensification is standard of care per all of the prostate cancer guidelines. However, in practice, data from the Veterans Affairs health care system, as well as from Medicare claims data suggests that ~45%-80% of men do not receive treatment intensification beyond ADT alone. The reason(s) for this lack of intensification are unknown and is an active area of research to provide further clarity. 

Treatment Intensification: Triplet Therapy

Two recent clinical trials have provided further evidence that treatment intensification with “triplet therapy” may improve survival even beyond standard of care doublet therapy. The PEACE-1 trial tested mHSPC patients treated with the “triplet” of ADT + abiraterone + docetaxel and found that they were 25% less likely to die versus patients treated with docetaxel + ADT (no abiraterone). The addition of abiraterone also prolonged the time to cancer progression by 2.5 years. The second trial was the ARASENS trial which tested the “triplet” of ADT + docetaxel + darolutamide (another oral second-generation anti-androgen) versus ADT + docetaxel (“doublet” therapy) in mHSPC patients. 

This trial found that patients treated with triplet intensification had a 32% decreased risk of death compared to doublet therapy patients. These patients also had improved time to castration resistance (when the PSA increases and disease worsens, despite hormone therapy), time to pain progression, time to symptomatic skeletal related events (i.e., bone fractures, needing radiation to the bones, etc.), and time to next cancer therapy. Importantly, for both trials, these improved outcomes of triplet therapy intensification were associated with only a modest increase in adverse events.

The decision on which therapies to combine can be complex and is influenced by several factors, including:

• Whether the patient is newly diagnosed with metastatic prostate cancer or has prostate cancer recurrence
• The amount of metastatic disease, classified as low vs. high volume
• Other patient health factors

Ultimately, if you are newly diagnosed with metastatic prostate cancer or have a new recurrence of your cancer that has spread (mHSPC), talk to your doctor about your treatment options. Ask if additional therapies beyond ADT alone may be right for you.

Progress in Prostate Cancer Research provides hope for finding a cure and the discovery of new treatments to minimize the impact of a man’s prostate cancer and maximize his quality of life. This regular ZEROHour supplement includes some of the latest research from the Prostate Cancer Foundation.

Written by Prostate Cancer Foundation. PCF is the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Since it was founded in 1993, PCF has funded more than 2,200 research projects at 245 leading cancer centers in 28 countries around the world. For more information, go to www.pcf.org or call 1-800-757-CURE.