The changing face of prostate cancer

Prostate cancer is the most common male malignancy in Western countries. Surgery and radiological procedures for localized prostate cancer offer the possibility for curative treatment. Prostate cancer also represents one of the most lucrative oncology indications for the pharmaceutical industry because drug-based treatment is often very effective at delaying disease progression, even in advanced disease, which encourages high-volume and long-term usage. The use of hormonal manipulation for advanced prostate cancer has been the mainstay of treatment for decades, but in the last 20 years, the increasing use of PSA screening in the and the consequent changes in treatment practice have driven changes in the approach to this disease. Increased screening in as well as changing global attitudes towards total androgen blockade and intermittent hormonal therapy are set to change the face of prostate cancer treatment and R&D still further.  Most recently the  and European authorities have approved the use of Taxotere for the treatment of hormone refractory prostate cancer which may prove to be one of the most important recent events in this arena.

Source: LeadDiscovery

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Introduction of PSA screening to change the landscape of prostate cancer management

The widespread introduction of Prostate specific antigen (PSA) screening in will occur over the next 10 years, leading to a US-style stage migration. PSA screening is available to all men in the under the Medicare patient support program, but European governments have taken a more cautious approach, as screening has not been proven to increase survival. While this is true, many studies have shown a significant increase in the diagnosis of earlystage tumors through screening, and such tumors are commonly acknowledged to have a better prognosis. The lack of any European consensus on screening has made its availability sporadic. A number of large-scale European screening trials are currently underway with the aim of determining the magnitude of any survival advantage that PSA screening may provide. The most notable of these is the ERSPC (European Randomized Study of Screening for Prostate Cancer trial, which will eventually enroll 200,000 men and will complete between 2006 and 2008, depending upon the survival difference between the screening and control arms. Analysts and field leaders believe that results of the ERSPC and other European trials will greatly impact the availability of screening within the major European pharmaceutical markets. Some opinion leaders believe that if the ERSPC trial finds an increase in disease-specific survival in the screened population, the political and public pressure is going to be so great that most countries will have to introduce screening as a healthcare policy.

From US studies, where PSA screening has been available since the mid-1980s, it is clear that the introduction of screening programs will produce an initial spike in the incidence rate resulting from the detection of asymptomatic tumors in addition to diagnoses from the traditional group of patients with symptomatic disease. This effect will last for a number of years until a large proportion of the screened population has had one or two PSA tests. The usage of screening will also gradually change the disease stage at presentation, as a greater proportion of asymptomatic localized tumors will be detected. This effect will result in an improvement in disease specific survival as an increasing number of patients undergo curative treatment.

A shift towards earlier diagnosis represents a significant challenge for European healthcare providers and physicians, most of whom are geared towards treating a larger proportion of patients with advanced disease. This challenge will also have to be met by manufacturers of PSA tests as well as companies involved in the development of radiation therapy devices and therapeutics. The introduction of screening is likely to increase the numbers of patients with recurrent disease, as aggressive disease tends to recur, no matter what the disease stage at diagnosis or treatment given. Many patients with aggressive disease, who would have otherwise escaped diagnosis until their tumor had become symptomatic, will be discovered at an early stage by more widespread screening. These individuals will often require treatment for locally recurrent disease and will, as such, represent a rapidly expanding new prostate cancer indication for manufacturers of hormonal products and developmental agents, or innovative treatments such as cryotherapy. By focusing on this area now, manufacturers will be able to establish themselves early and benefit from increasing usage as the recurrent disease population expands.

Changing attitudes to total androgen blockade

Historically, reviews and meta-analyses investigating the role of total androgen blockade (the use of an LHRH antagonist and an anti-androgen in combination) versus LHRH antagonist monotherapy in advanced prostate cancer have concluded that the all clinical benefit of the combined regimen is not great enough to justify subjecting patients to the increased side effects of total androgen blockade. However, interviews with clinicians have shown that total androgen blockade was the most commonly used hormonal drug regimen for metastatic disease in all the countries investigated, with the exception of the . Although LHRH antagonist monotherapy predominates over total androgen blockade in patients with localized disease, this pattern reverses in patients with locally advanced disease, a trend which becomes even more evident in patients with metastatic cancer.

The first and most important reason for the high volume usage of total androgen blockade is that most urologists believe that, contrary to the majority of the medical literature, there is a significant survival advantage to using total androgen blockade over LHRH antagonist monotherapy. Authors of literature reviews have historically recommended the use of LHRH antagonist monotherapy over total androgen blockade because of additional toxicity associated with the latter. However, many of these studies were conducted in the early 1990s prior to the availability of Casodex which, in contrast to earlier agents, is not viewed as being excessively toxic. As physicians have become familiar with the use of Casodex the opinion that total androgen blockade is acceptable to the patient has apparently become more widespread. A large-scale trial comparing total androgen blockade with LHRH antagonist monotherapy trial using a low toxicity non-steroidal anti-androgen would however help crystalize this view.

Intermittent hormonal therapy is destined to alter disease management and pharmaceutical approaches to prostate cancer

Most prostate tumors are androgen-dependent, requiring testosterone to grow. As such, the use of continuous anti-hormonal agents such as LHRH antagonists and antiandrogens is commonplace when systemic treatment is required. Although therapeutic options have improved, long-term androgen manipulation still has many acute and chronic side effects. Acute toxicities include hot flashes, asthenia, sexual impotence and loss of libido and chronic toxicities include osteoporosis, loss of muscle mass, depression, anemia, malaise, fat accumulation and impaired mental function. A further and more serious problem is that the average patient with metastatic prostate cancer develops hormone refractory disease after just two years of treatment. This has led some researchers to investigate intermittent hormonal therapy, the use of a total androgen blockade regimen until disease control is achieved, followed by a period when the patient receives no drug therapy that lasts until disease recurrence. In theory, this should maintain the hormone-dependence of the tumor for longer. At the same time, patients also get a break from the acute symptoms of androgen suppression and may be less likely to suffer chronic symptoms.

The use of intermittent hormonal therapy is still experimental, with no data as yet returned from randomized multicenter trials. The available published data to date has however been positive, showing that intermittent hormonal therapy provides an improved quality of life with at least equivalent disease control. The problem is that there is no consensus opinion, as yet, on when to begin and when to stop the total androgen blockade regimen. However, this has not stopped urologists from most countries using intermittent hormonal therapy in selected patients. The volume usage of total androgen blockade is likely to increase substantially if the four large-scale randomized clinical trials currently in progress show a quality of life or time to hormone refractory disease advantage for total androgen blockade.

Most opinion leaders have had experience of using intermittent hormonal therapy, however their views vary considerably. Although some see this approach as being able to improve quality of life, others do not believe that it has been sufficiently characterized. The need to address this situation is becoming greater since the duration of drug exposure is increasing in parallel with earlier diagnosis. Analysts believe that intermittent hormonal therapy has the potential to become very heavily used in markets such as the US, Germany and France which either have a strong focus on quality of life or are open to the introduction of new technologies and techniques. Cost-contained markets may also implement the use of intermittent hormonal therapy because of the lower dosing and therefore diminished spend on hormonal drugs compared to continuous treatment. Conversely further uptake of intermittent hormonal therapy, should it occur, is likely to significantly reduce the revenue obtainable from pharmaceutical manufacturers' prostate cancer franchises. Another impact might be the less common usage of long-term depot formulations of LHRH antagonist drugs (those exceeding three months) as prescribers try to maintain their flexibility in determining the switch between on- and off-phases of treatment.

Currently available data would suggest that the three major intermittent hormonal therapy randomized trials in , the and will return data that shows that at least some patients, likely to be those with a good prognosis, suffer fewer long-term side effects and gain relief from acute side effects when on intermittent therapy. In the face of such strong evidence, it is believed that many physicians will begin using intermittent treatments, although others may wait until a consensus opinion exists on the most appropriate regimen. Manufacturers with marketed and pipeline agents should be prepared for this potential change in treatment strategy. Reformulation may be an option for manufacturers of LHRH antagonists; so that they may be rapidly removed from the patients system, such as nasal or epidermal delivery, or produce a formulation that can have its clinical activity rapidly curtailed should the patient reach PSA nadir. Such products may gain uptake amongst physicians by virtue of their ease of use in intermittent hormonal therapy protocols, while also allowing manufacturers to charge a premium for the new formulation, reducing the revenue impact of patients receiving lower total doses of hormonal products on intermittent hormonal therapy compared to continuous treatment. In particular, companies developing LHRH antagonists should consider developing these products for use in intermittent hormonal therapy regimens.

New options once hormonal therapy has failed

Even though more patients than ever before are now being diagnosed in early-stage disease and are receiving treatment of curative intent, around 40% to 50% of prostate cancer patients will eventually develop hormone refractory prostate cancer, that is, a tumor that does not respond to hormonal drug therapy. A all proportion of patients will be diagnosed with hormone refractory disease, but most patients will become hormone refractory following years of testosterone deprivation therapy. For those patients with hormone refractory prostate cancer, the prognosis is poor, with average survival estimated at just 18 months.

There are just two approved agents for the treatment of hormone refractory prostate cancer: estramustine and mitoxantrone. Neither of these agents are effective in treating the tumor itself, but were approved on the grounds that they have a palliative effect on disease symptoms. However, as cytotoxic drugs, both of these agents have poor toxicity profiles, a factor that must be considered given that neither has been shown to improve survival. This has made hormone refractory prostate cancer a tumor indication of very high unmet need, leading to many pharmaceutical manufacturers trialing their cytotoxic and innovative agents in this indication, but hormone refractory prostate cancer has proven unresponsive to many of these drugs. However, with the investigation of some of the third generation cytotoxics such as Pierre Fabre's Navelbine (vinorelbine), BMS' Taxol (paclitaxel) and Aventis' Taxotere (docetaxel), significant tumor responses have been observed. Of these products, Taxotere is causing the most interest amongst medical oncologists, primarily because clinical trial data to date shows that Taxotere is the most efficacious regimen for the treatment of hormone refractory prostate cancer yet reported.

Prostate cancer opinion leaders are very positive about Taxotere. A recent survey of prescribers found that Taxotere is already commonly prescribed for hormone refractory prostate cancer. Taxotere was the most commonly used agent estramustine and mitoxantrone in most major pharmaceutical markets. On average, Taxotere was used in 13% of hormone refractory prostate cancer patients even prior to approval. In particular, US oncologists are prescribing Taxotere in the hope of delaying disease progression and increasing median survival. Taxotere, whether in combination or monotherapy, was prescribed to 25% of hormone refractory prostate cancer patients in the . The uptake of Taxotere in the is likely to have been boosted by the general acceptance of new and innovative therapies amongst US physicians. Furthermore, the market is the least cost-conscious of the seven major markets and off-label usage does not affect reimbursement for Taxotere.

Taxotere was approved by the FDA in May 2004 for the treatment of hormone refractory prostate cancer in combination with prednisone. This was followed by approval in in November, 2004. The European Commission approved Taxotere on the basis of results from the landmark phase III clinical trial, TAX 327, which demonstrated that a Taxotere-based regimen significantly reduced the risk of death by 24% in men with hormone refractory metastatic prostate cancer. Investigators in the TAX 327 trial also reported that Taxotere significantly improved patients' PSA response by 43% and improved pain response by 59%, relative to mitoxantrone. In the TAX 327 trial, investigators reported that Taxotere was well tolerated.

Opinion leaders now believe that taxotere and estramustine will soon be the new gold-standard treatment for hormone refractory prostate cancer as it will be the first time any drug has shown an extension in survival. Taxotere monotherapy could also become commonly used in patients not able to tolerate the estramustine. In light of this advance, companies with agents in development for the treatment of hormone refractory prostate cancer should investigate the activity of their drugs in combination with Taxotere.

A rosy future for prostate cancer therapeutics

All in all the future for prostate cancer patients is promising. Men are set to benefit from ever improving screening protocols leading to earlier diagnosis. With the advent of improved anti-androgens, clinicians will be more accepting of total androgen blockade and evolving experience with intermittent therapy will diminish adverse effects and prolong efficacy. Even when patients are faced with progression towards hormone refractory disease they may be able to benefit from the latest weapon in the armory of prostate cancer clinicians, Taxotere.

The data and conclusions in this feature are discussed in depth in our new featured reports:

• Local and Locally Advanced Prostate Cancer
• Metastatic And Hormone Refractory Prostate cancer

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