A brief history of prostate cancer treatment

In the National Archaeological Museum of Lisbon, Portugal, a mummified middle-aged male of ancient Egypt is stored. Not long ago, scientists studied this corpse and found that there are many high-density round tumors between the pelvis and the lumbar spine, which is a typical manifestation of prostate cancer.

More than 2,000 years have passed from ancient Egypt to the present. Today, prostate cancer is already one of the most common cancers in men. One out of every nine men will develop prostate cancer in their lifetime. However, as revealed by an authoritative report from American Cancer Society (ACS), the mortality rate of prostate cancer patients in 2014 was sharply reduced by 51% compared with 1993. This reflects the tremendous progress of treatment in the past few decades. This article portrays the history of therapies used for treating prostate cancer in humans.

Stage 1: Hormone therapy

It is hard to imagine that prostate cancer was considered "a very rare disease" when it was first diagnosed in 1853. In the next century, scientists and doctors have made very limited progress. In the 1940s, prostate cancer was synonymous with death. After diagnosis, the patient's survival time was only 1-2 years. However, the year of 1941 marks a historical transition point when Professor Charles Huggins of the University of Chicago and his colleagues published several papers revealing the relationship between hormones and the prostate. In theory, the growth and development of the prostate depends on the action of androgens. Therefore the growth of prostate cancer can be inhibited by inhibiting the function of androgen. As they have previously envisaged, they later found that by injecting estrogen into patients, it can effectively delay the progression of prostate cancer.

Many scientists believe that this is the first time humans have successfully controlled prostate cancer by using certain chemicals. Professor Huggins won the 1966 Nobel Prize in Physiology or Medicine, as his discovery of this hormone therapy unveiled the curtain of endocrine therapy for prostate cancer. In the following decades, a variety of drugs that inhibit androgen appeared.

Stage 2: anti-androgen therapy 

Over time, people gradually discovered that after castration treatment, cancer cells will gradually adapt to this low hormone level environment and continue to grow. New therapies need to be discovered, among which "anti-androgen therapy” is the most known. Unlike previous therapies, these therapies act directly on the androgen receptor, inhibiting androgen binding to it. In fact, as early as 1989, the first generation of anti-androgen therapy factor was approved by the US FDA. However, early anti-androgens have a low affinity for androgen receptors, thus limiting the use of such therapies. 

In 2012, Xtandi (enzalutamide), jointly developed by Medivation (later acquired by Pfizer) and Astellas, was approved for marketing. As a new generation of anti-androgen therapy, it inhibits both androgen binding to its receptors and inhibits androgen receptors from entering the nucleus, preventing it from initiating downstream biochemical pathways. In patients who suffer from castration-resistant prostate cancer and whose condition has metastasized and chemotherapy is powerless, half of the patients can survive for 18.4 months if they receive Xtandi treatment. This number was nearly five months longer than the placebo control group. In 2018 and 2019, Janssen's Erleada (apalutamide) and Bayer's Nubeqa (darolutamide) were also approved by the FDA for listing in the army of castration-resistant prostate cancer.

Stage 3: emergence of innovative therapies and targeted therapies

Cancer cells eventually develop resistance to hormone therapy in a variety of ways. As a result, researchers are also developing innovative treatments that are not based on androgen signaling pathways. One of these innovative therapies is the world's first "therapeutic" tumor vaccine Provenge (sipuleucel-T). As an individualized therapy, it separates dendritic cells (an antibody-presenting cell) from the patient's blood and co-cultures with a specific fusion protein. The fusion protein is divided into two parts, one is prostatic acid phosphatase (PAP), which is the main antigen on prostate cancer cells; the other is an immune signaling factor that promotes the maturity of these antibody-presenting cells. Subsequently, these processed cells, which are able to effectively recognize prostate cancer antigens, are returned to the patient to activate immune T cells to find and kill cancer cells that express PAP. Phase 3 clinical trial results also confirmed that it can significantly improve the median survival of patients. Fortunately, a recent study found that these immune cells activated by tumor vaccines have long-term memory and are expected to have long lasting therapeutic effects.

In addition to the immunotherapy described above, targeted therapies developed based on the molecular characteristics of cancer have also become the latest trend in cancer treatment. In prostate cancer, the latest breakthrough is the use of PARP inhibitors. For example, in August this year, MSD and AstraZeneca announced that Lynparza (olaparib) has achieved positive results in a phase III clinical trial of men with metastatic castration-resistant prostate cancer (mCRPC).

Summary: In the future, prevention and new therapies are the mainstream. 

Currently, a protein called prostate specific antigen (PSA) can be used for early screening, adjuvant diagnosis, therapeutic monitoring, and prognosis of prostate cancer. At the same time, innovative therapies are also being actively explored. It is believed that by combining early screening techniques and innovative therapies, prostate cancer may be finally eradicated one day.