Combining hormone therapy with additional therapies – an update

This review evaluated current evidence on combination therapies for metastatic hormone-sensitive prostate cancer (mHSPC). Authors concluded that results are promising for the combination of taxane-based chemotherapies and alternative hormone therapies with androgen deprivation therapy (ADT).

ADT is a type of hormone therapy that targets male hormones (such as testosterone) active in cancer growth. Reducing androgen levels can dramatically improve survival among prostate cancer patients. ADT involves the surgical removal of the testicles (orchiectomy) or drug therapy. Drug therapies either lower the production of testosterone in the body (GnRH agonists) or block the action of androgens (antiandrogens). ADT is currently the standard of care for advanced prostate cancer, including prostate cancer that has spread to distant organs (metastatic).

Many patients, however, stop responding to hormone therapy over time. This is called hormone-resistant prostate cancer. Taxane-based chemotherapy, such as docetaxel (Taxotere), or alternative hormone therapies, such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi), are often added in hormone-resistant prostate cancer. However, recent evidence is suggesting that adding secondary therapies to ADT early for hormone-sensitive prostate cancer may increase survival. This is in contrast to waiting until cancer progresses and becomes hormone-resistant.

The aim of this review was to summarize recent findings on primary therapies for metastatic hormone-sensitive prostate cancer (mHSPC).

Approximately 5% of cases treated with ADT are treated with orchiectomy. It has the advantage over drug therapies in that it lowers testosterone levels fast and reliably. However, the effects of orchiectomy and ADT drug therapies are similar. One analysis of 10 separate trials reported no differences in disease progression and overall survival between orchiectomy and ADT drug therapies.

Since ADT is associated with significant side effects, the timing of treatment has been the focus of much investigation. For patients with symptomatic mHSPC, ADT should be started immediately. Patients without notable symptoms may delay treatment to postpone side effects. However, one analysis involving 4 separate trials and 3,065 mHSPC patients found that early ADT reduced prostate cancer-related deaths compared to delayed ADT. Administering ADT with breaks between treatments (intermittent ADT) is another strategy to reduce side effects. Intermittent ADT is often associated with better quality of life and similar survival in mHSPC. Not all patient may be eligible for intermittent ADT.

Two separate clinical trials reported a benefit of adding docetaxel chemotherapy early to ADT for mHSPC. Disease progression and overall survival were significantly improved compared to ADT alone. On average, mHSPC patients treated with additional docetaxel were between 24 to 39% more likely to survive the study follow-up (average 6 years). However, another trial reported no significant benefit of adding docetaxel early. A combined analysis of these 3 trials showed that adding docetaxel early to ADT was beneficial for mHSPC, but not for non-metastatic HSPC. 

Alternative hormone therapies with enzalutamide and abiraterone acetate have shown significant survival benefits in advanced prostate cancer. Enzalutamide is now widely used for hormone-resistant prostate cancer. Clinical trials investigating the effects of enzalutamide and abiraterone acetate in combination with ADT for mHSPC are ongoing. 

Exercise, smoking cessation, calcium and vitamin D supplements, as well as bisphosphonates are often recommended to prevent bone fractures during ADT. Radium-233 is a type of radiation therapy that has shown to improve survival in men with metastatic prostate cancer. The effectiveness of radium-233 for mHSPC is currently being explored.

Authors concluded that adding secondary therapies early to standard ADT are promising therapeutic options for treating mHSPC.