Breakthroughs for Hormone-Resistant Prostate Cancer

BY MARK SCHOLZ, MD

The value of a new medical treatment is gauged by the seriousness of the problem it overcomes.  Hormone-resistant prostate cancer—that is, prostate cancer that has become resistant to testosterone inactivating pharmaceuticals (TIP) like Lupron, Casodex, Zoladex, Firmagon, Trelstar and Eligard—is certainly qualifies as serious.  The development of two medications to treat hormone resistance is significant.  Erleada, which is a new medication, and Xtandi, which is a repurposed medication, have been shown as remarkable agents against tough-to-treat, TIP-resistant prostate cancer.

The Efficacy of Standard TIP

Many people fail to appreciate TIP’s amazing anticancer effects.  Within roughly six months of starting TIP, 99.9% of the prostate cancer cells die!  PSA usually drops to undetectable levels and remains there for an average of ten years!  No other anticancer therapy provides such a durable response.  TIP’s remarkable anticancer efficacy is why some experts consider prostate cancer to behave more like a chronic illness than a cancer.

The Implications of TIP Resistance

TIP is by far the most popular type of medication for men whose cancer has relapsed after surgery or radiation.  TIP resistance, defined as a rising PSA while receiving TIP, is a serious and well-known harbinger of impending metastases, progressive cancer and death.  Resistance to TIP should generate a profound level of concern for the patient’s health and well-being.

Outdated Thinking Can Be Dangerous

Historically, frightening implications of hormone resistance—that is, a rising PSA while taking TIP— have been downplayed.  Since there was really no effective treatment to offer anyway, patients readily accepted assurances that “everything is OK.”  Typically, patients have been on TIP for many years with great PSA control.  When PSA increases, since it is just a blood test, they tend to be relatively unconcerned.  Perhaps they are “lulled to sleep” by so many quiet and uneventful years of taking TIP.  But now, with the advent of Erleada and Xtandi, doctors no longer need to minimize the seriousness of TIP resistance.  We have effective therapy to tackle the problem of hormone resistance head on.

The Cause of TIP Resistance

Testosterone stimulates cancer cell replication by activating growth genes found on DNA in the cancer cell’s nucleus.  Doctors used to assume that hormone-resistant prostate cancer cells somehow learned to grow without testosterone.  But research has discovered that prostate cancer cells still require testosterone to proliferate.  Instead of obtaining testosterone through the blood stream (originating from the testicles) the cancer cell itself manufactures its own testosterone internally!  Once researchers realized this was occurring, they invented new pharmaceutical agents designed to block testosterone’s access to the cancer cell’s nucleus.  Erleada and Xtandi, two oral medications approved by the FDA, “wall off” testosterone’s access to the nucleus, keeping it away from the DNA. Without a testosterone signal to activate cell growth, cancer progression is halted.

The Importance of Starting Treatment Promptly

Numerous cancer studies show that effective anticancer therapies work better against smaller tumors than larger ones.  Why is this? First, as the number of cancer cells increase the odds increase that the cancer will mutate into more malignant, treatment-resistant forms.  The other issue relates to the immune system. The immune system is constantly battling to inhibit cancer growth, but cancer cells have ways to suppress the normal activity of the immune system.  When tumors grow larger, the cancer’s capacity to have an inhibitory effect on the immune system increases.

The Mechanics of Detecting Hormone Resistance

Men taking TIP should be checking their PSA every three months.  If the PSA starts to increase, the PSA should be checked even more frequently, perhaps monthly.  If sequential checking confirms a consistent pattern of rise, then Erleada or Xtandi should be started right away.  Both medications are oral agents. With each, patients take four pills once a day.  The treatment effect is usually quite rapid. PSA levels should start declining within a month or two at the most.

How Big is the Anticancer Effect of Erleada and Xtandi?

Over two thousand men with hormone-resistant prostate cancer participated in two randomized trials comparing Erleada or Xtandi with a placebo.  Neither the doctors nor the patients knew which patients were taking the active medication.  After starting treatment (or the placebo), men were placed on surveillance and underwent repeated bone scanning every three months.  On average, the men treated the old-fashioned way, i.e. those who received essentially no treatment in the form of a placebo, developed bone metastases in a little more than a year. On the other hand, it took the men who received Erleada or Xtandi an average of more than three years to show metastases.

Side Effects of Erleada or Xtandi

Since Erleada and Xtandi work by blocking the activity of testosterone, their side effects tend to be very similar to the side effects of TIP.  In fact, many men who have been taking TIP for many years won’t notice any new side effects at all with Erleada or Xtandi.  Just to review, there is a long list of potential TIP-related side effects, including muscle loss, fatigue, impotence, low libido, breast enlargement, depression, osteoporosis, memory problems, weight gain, and hot flashes.  Unlike Casodex or Zytiga, potential liver problems are not an issue with Erleada and Xtandi.  However, both medications should be withheld in men with a previous history of seizures.  Finally, both medications have the potential for a greater degree of fatigue than is commonly seen with TIP.

The recent FDA approval of Erleada and Xtandi for treatment of men with early hormone resistance is an important breakthrough with major implications for delaying prostate cancer progression.  To ensure that these two new powerful drugs are used in an optimal fashion, men who are taking TIP should check their PSA levels every three months.  They should start treatment with Erleada or Xtandi immediately if the PSA is consistently rising.  The good news is that these agents are both effective and well-tolerated.  Many men will not be able to discern any additional side effects beyond what they had already been experiencing with TIP.

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