Xtandi as Primary Therapy

MARK SCHOLZ, MD

The largest oncology market in the world is the early-stage prostate cancer market. Every year, 80,000 men undergo surgery. Even greater numbers are treated with IMRT, seed implants, cyberknife and proton therapy.

What about Hormones?
Hormone therapy is another popular treatment approach, especially for older men. For example, the Capsure database indicates that hormone blockade is used more commonly than radioactive seeds.  Randomized clinical trials also indicate that intermittent hormone therapy is feasible:  Men who stop hormone therapy and take “treatment holidays” have identical survival rates to men who stay on continuous treatment.

Standard Treatment is Deplorable
Since PSA screening started in the early 1990s, surgery and radiation have been all the rage.  Aggressive treatment has succeeded in reducing annual prostate cancer mortality by half a percent. Now “only” 2.5% of men die of prostate cancer. Previously, prior to the advent of PSA screening, 3% of men died from prostate cancer. The “cost” of achieving this mortality reduction, however, should be measured in terms of diminished quality-of-life. The frequency of serious side effects is typically under-appreciated. For example, at the highest quality treatment centers only 5% of men recover sexual function similar to what they enjoyed prior to treatment. 7% of men are grossly incontinent; 50% have stress incontinence and 20% chronically ejaculate urine.

The reason for such a minuscule impact of local treatment on survival is obvious: Surgery and radiation are only effective when implemented prior to metastases. Ironically, until metastases occur, local treatment is unnecessary. After metastases, local treatment is ineffective.  Logically, early therapy with an anticancer agent with both local and systemic effects will result in better cancer control.

Active Surveillance is Now Mainstream
It is now known that Low-Risk disease (Gleason 6, PSA < 10, Stage T1c or T2a) can safely be monitored with active surveillance. At worst, active surveillance has the positive effect of delaying treatment and postponing treatment-related side effects like impotence and incontinence. With delayed local treatment, men benefit from the fact that medical technology is continually improving.  The best case scenario of active surveillance is when cancer never progresses and men are able to avoid treatment indefinitely.

Widely-accepted active surveillance methodology relies on periodic random 12-core needle biopsies.  Now encouraging studies are reporting that 3T multiparametric MRI detects high-grade disease more accurately than biopsy.  Also, new computerized imaging technology enables doctors to record the exact location of the cancer within the prostate gland so that areas of known disease can accurately be resampled with targeted biopsies.

Hormone Therapy Causes Remission of Localized High-Risk Disease with Reversible Side-Effects
A study using a six-month induction course of abiraterone (Zytiga) shows complete pathologic remission or close to complete remission in a third of men with High-Risk disease. Logic predicts that complete response rates will be substantially better in men with Intermediate-Risk prostate cancer.

For the most part, side effects of hormone therapy are reversible or preventable—hot flashes, breast enlargement, osteoporosis, and erectile dysfunction respond to DepoProvera, Femara, Prolia and Viagra respectively. Muscle atrophy can be counteracted with strength training. Low libido dissipates after therapy is stopped. Careful diet averts weight gain.

However, the reversibility of hormone therapy depends on the resumption of normal testosterone production after treatment is stopped. Unfortunately, LHRH agonists, the traditional hormone medications employed, often induce lingering low testosterone levels. Some men, particularly those over 70, are saddled with permanently low testosterone.

Xtandi is Well-Suited to Intermittent Administration
Xtandi has several potential advantages over LHRH agonists.   First, it is more potent.  Studies show that Xtandi has notable activity even after cancer had developed resistance to LHRH agonists. Second, Xtandi blocks testosterone activity rather than suppressing testicular production. Therefore the risk of delayed testosterone recovery or long-term testicular atrophy is circumvented.  Third, though perhaps this is a relatively small issue, most men would rather take a pill than a shot.

An Observational Trial of Intermittent Xtandi Could Revolutionize Intermediate-Risk
Laurence Klotz, M.D. prospectively accrued men with Low-Risk (and some Intermediate-Risk) prostate cancer to a simple observational trial starting in the mid-1990s.  By simply reporting a very favorable ten-year mortality rate he brought about a total change in clinical practice patterns in the United States and throughout the world.

Intermittent hormone therapy as primary treatment is certainly feasible for localized prostate cancer.  Active surveillance methodology has been refined with improved imaging.  New genetic tests can estimate cancer aggressiveness with more accuracy. The animus to delay treatment, even for a few years, is increasing as the pace of technological innovation accelerates and the hope for the discovery of less toxic treatment increases. Now, with the recent FDA approval of this more potent, more convenient oral agent that is free of lingering effects, the impetus for men to embark on a six-month induction course of Xtandi followed by active surveillance will be even greater.

Selecting a Meaningful Endpoint for an Observational Clinical Trial
Published studies already document excellent survival with primary hormone therapy (see attached). Hence, the most meaningful clinical outcome measure of Xtandi efficacy would be its capacity to forestall or delay local treatment. The objective endpoint, therefore, should measure the number of months or years before local therapy is required, starting from the date of initiating Xtandi and ending when (and if) local therapy is ultimately implemented.

While complete avoidance of local treatment may be a frequent occurrence (in the men who show durable responses to a single cycle of Xtandi) it can be anticipated that men who have locally recurrent disease and whose initial experience with Xtandi was tolerable, may elect to use repeated cycles of Xtandi at the time of recurrence rather than risking the potentially irreversible side effects of local therapy. Conversely, the men most likely to select local therapy are those who experience a particularly short treatment holiday or suffer more severe hormone-related side effects.

A six-month course of Xtandi can also function as a “disease-related stress test.” Men in the subgroup manifesting either high PSA nadir or rapid disease recrudescence after treatment are those most likely to harbor an aggressive prostate cancer variant. Thus, this initial “test” using Xtandi will help ensure that men referred for radical local therapy are those who actually need it.