Of course, as do other cancers, prostate cancer can present with or can develop metastatic disease as part of its natural history. It is this that we hope to prevent and, if this develops, there is the possibility of mortality. Almost always, distant metastasis in prostate cancer is to bone.

I have commented previously that prostate cancer is analogous to breast cancer in many respects. Interestingly, the first site of distant metastasis for hormone-sensitive breast cancer is usually bone as well. This stems from the fact that both share an origin from reproductive hormonal stimulation. In the case of breast cancer, the disease most often develops from excess unopposed estrogen exposure, and as the prostate is similarly part of the reproductive tract in men, cancer in the prostate is related to the overproduction of androgens, specifically testosterone and dihydrotestosterone, a breakdown product of testosterone. While the literature is not crystal clear on the subject of testosterone levels and risk of prostate cancer, it does seem clear that prior elevated levels of testosterone are associated with an elevated risk of prostate cancer.

Nonetheless, for both breast cancer and for prostate cancer, once metastatic disease has developed, one of the earliest discovered efficacious treatments was removal of the hormone-producing organ. Thus, for premenopausal women with metastatic hormone-sensitive breast cancer, bilateral oophorectomy (removal of the ovaries) is an extremely effective treatment. Likewise for men, one of the earliest, if not the earliest, treatment for advanced prostate cancer was bilateral orchiectomy (removal of the testicles), which was introduced by Charles Huggins in 1941.

The surgical options for treatment of these advanced cancers are not, nowadays, particularly popular despite their effectiveness and relative ease—one does not need further ongoing treatment for extended periods. Radiation therapy could be utilized for the same purpose, to sterilize the ovaries or testicles, but again is not widely utilized. (It is used in some low-resource countries for this purpose.) Instead, we have developed pharmacologic therapies—various hormonal treatments for breast cancer and anti-androgenic treatment for prostate cancer.

Indeed, the first systemic pharmacologic therapy of any kind in oncology was the use of diethylstilbestrol (DES), a synthetic estrogen product, for the treatment of advanced prostate cancer, introduced after World War II. While it was extremely efficacious, it was also, as one might expect, extremely feminizing, with significant resultant gynecomastia (breast tissue development).

Since prostate cancer is thought to be dependent on androgens for its growth and proliferation, the logical first step in treating advanced prostate cancer is anti-androgen or androgen deprivation therapy (ADT). The initial approach (in preference to surgical castration or to estrogens) was drugs such as flutamide or bicalutamide, oral agents that inhibited the binding of dihydrotestosterone to the androgen receptor but did not modify the testosterone level. They were sometimes used together with luteinizing hormone release hormone (LHRH) agonists, such as Lupron (leuprolide), which did interfere with testosterone production. LHRH is an intermediary hormone between the pituitary and the ultimate effector cells in the testes where the testosterone was produced. There were also LHRH antagonists, either of which are effective as ADT, such as degarelix and relugolix. While they are probably pretty similar in efficacy, Lupron has predominated in use for ADT.

Another drug in this pathway is abiraterone, which is oral and administered in conjunction with prednisone. It suppresses the production of androgens, including testosterone, and so when used together with the usual ADT drugs (flutamide and Lupron), it leads to a more profound reduction in testosterone levels and thus improves progression-free survival over ADT alone. Another drug, enzalutamide (XTANDI), blocks the binding of testosterone to the androgen receptor on the cancer cell and thus inhibits proliferation. It is also effective, in combination with ADT, in prolonging PFS and improving mortality; randomized trials show an increase of 5% or more in five-year survival over ADT alone.

For newly diagnosed metastatic prostate cancer, treatment should be individualized, but almost all patients should get a combination of ADT plus enzalutamide or abiraterone. If the disease is high risk, chemotherapy should be added; the chemotherapy drug of choice is Taxol (docetaxel). Until the introduction of the taxane class of drugs of which Taxol is a member, chemotherapy was thought to be ineffective for advanced prostate cancer. The TAX-327 trial, published in the New England Journal of Medicine in 2004, established the efficacy of Taxol for metastatic prostate cancer. The trial randomized 1,006 men who had progressed on hormonal therapy of prostate cancer to every-three-week Taxol, weekly Taxol, or mitoxantrone. All subjects received 10mg of prednisone daily and were continued on ADT. The overall survival was 19.2, 17.8 and 16.3 months for the three arms, respectively, and the three-year survival rates were 18.6%, 16.6% and 13.5%, respectively. Thus, Taxol has been added to the armamentarium for those who have failed hormonal therapy.

Several trials have also evaluated the addition of Taxol to ADT for patients at the time of initial diagnosis with metastatic prostate cancer. A meta-analysis published in Lancet Oncology in 2023 combined data from three randomized trials on 2,261 patients followed for a median of 72 months which compared Taxol/ADT to ADT alone, and found that the overall survival improvement was 0.79 (95% confidence interval 0.70-0.88), a 21% improvement in survival. The benefits appeared to be restricted to those with an increased volume of disease.

I should note that other new drugs are also currently in the pipeline for advanced prostate cancer.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.