Management of Metastatic Disease

Key

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Benefits of MAB with bicalutamide in patients with metastatic disease

Prostate Cancer Update 2005 (3)

DR KLOTZ: Our analysis integrated the results from trials with a common treatment arm in situations in which it’s no longer feasible to conduct a placebo- controlled trial. Dr Schellhammer compared bicalutamide to flutamide with goserelin or leuprolide and demonstrated a 13 percent reduction in the risk of death for the patients receiving bicalutamide compared to those receiving flutamide.

We integrated those data with the results from the meta-analysis of the Prostate Cancer Trialists’ Collaborative Group, which demonstrated a significant eight percent reduction in the risk of death for patients treated with flutamide plus castration compared to those treated with castration alone. The flutamide/ castration arm can be cancelled out, and you end up with a comparison of bicalutamide plus castration to castration alone even though they have never been directly compared. This analysis demonstrated a 20 percent reduction in the risk of death for patients treated with bicalutamide plus castration.

Use of maximal androgen blockade

Prostate Cancer Update 2005 (1)

DR PETRYLAK: The survival data from the SWOG studies — particularly SWOG- 8494, in which Dave Crawford was the principal investigator — showed approximately a three-month improvement in survival in favor of combined blockade compared to an LHRH agonist alone.

I use maximal androgen blockade. Certainly, we’ve treated patients with more aggressive therapy for less of a survival benefit. I believe it can’t hurt. And if it can’t hurt and has a possibility of improving survival, I will use the combined blockade with bicalutamide, which is the easiest drug for me to administer and for the patient to receive.

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Intermittent versus continuous androgen deprivation

Prostate Cancer Update 2005 (3)

DR CRAWFORD: SWOG-S9346, which has been ongoing for a number of years, has accrued about 2,000 patients. Men with newly diagnosed, untreated metastatic disease receive combined androgen ablation. At nine months, if their PSA drops below 4 ng/mL, they are randomly assigned to continuous or intermittent therapy. With intermittent therapy, the patient resumes hormonal therapy when his PSA goes up to a predetermined level — usually half of the baseline level or 10 ng/mL.

The whole idea is to provide a hormonal therapy holiday to reduce toxicity and costs. Integrated in that trial is the use of bisphosphonates, particularly zoledronic acid, to evaluate their effects on bone disease.

We have enough data suggesting that intermittent therapy is probably not going to make the patient’s scenario worse; at least that’s what has been reported.

Whether it’s going to be better is unknown. If the benefit is the same as for continuous therapy, it’s a no-brainer that intermittent therapy would be the choice, since patients can have a drug holiday with fewer side effects and less expense.

Earlier integration of medical oncologists in management

Prostate Cancer Update 2005 (1)

DR PETRYLAK: In the community, urologists usually attempt a couple of hormonal manipulations and then send their patients to the oncologist. The optimal time to start chemotherapy is a bit of an art, and no FDA guidelines delineate the proper time to start chemotherapy.

Not all patients with hormone refractory disease should start chemotherapy. I believe patients should see an oncologist initially, but they should never lose contact with their urologist. The urologist is the primary caregiver who diagnoses the disease and may have removed the prostate. These patients will continue to depend on their urologists when problems and complications develop from the prostate cancer, such as urinary tract obstruction, stinting and transurethral resections of the prostate.

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Incorporating chemotherapy into the treatment of prostate cancer

Prostate Cancer Update 2005 (1)

DR DICKER: Two trials reported at ASCO 2004 demonstrated a survival advantage in patients with hormone-refractory disease receiving docetaxel-based therapy. Docetaxel is being extensively evaluated in clinical trials in patients with metastatic disease that is not hormone refractory. Various randomized trials are evaluating hormones with or without chemotherapy in the nonrefractory population. We don’t know if chemotherapy — particularly docetaxelbased chemotherapy — combined with hormones is beneficial in patients with locally advanced disease. Chemotherapy regimens involving taxanes and estramustine have been evaluated, but estramustine has a number of side effects, including deep vein thrombosis. Those studies have been plagued with toxicities and haven’t really moved forward.

Prostate Cancer Update 2005 (1)

DR PETRYLAK: Our first studies evaluating docetaxel with estramustine were performed in the laboratory in 1995. We were excited by what we saw in vitro and moved forward into a Phase I study that opened in February of 1996.

One of the old jokes about Phase I studies is that the first patient responds but then nobody else does. Well, the opposite happened in that study: The first patient didn’t respond, but nearly every subsequent patient did. We saw promising responses in patients who were heavily pretreated. Median survival was close to 24 months, and that was the highest reported median survival of any study at that time.

This background provided the basis for SWOG-9916, which is a randomized trial comparing docetaxel/estramustine to mitoxantrone/prednisone in men with progressive androgen-independent prostate cancer and soft-tissue or bony metastases. These were not the asymptomatic patients with rising PSA only. They had to progress by one of three criteria: bone scan, CT or PSA. The trial opened in October 1999 and closed in January 2003. We demonstrated a 20 percent reduction in the rate of death in favor of those patients who received docetaxel/estramustine; however, estramustine- related toxicity was problematic and included deep venous thromboses, cardiovascular events and nausea.

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A related and important trial was TAX-327, which compared docetaxel weekly or every three weeks plus prednisone to mitoxantrone/prednisone. Survival was improved with every threeweek docetaxel. The data from both studies demonstrate for the first time that we have a chemotherapeutic agent — docetaxel — that results in prolonged survival for men with hormone-refractory prostate cancer.

Because the estramustine-related toxicity was problematic and the median survival and hazard ratios are similar for docetaxel/prednisone and docetaxel/ estramustine, the FDA has recommended docetaxel/prednisone as the standard of care for hormone-refractory metastatic prostate cancer.

The FDA approved docetaxel for patients with hormone-refractory metastatic prostate cancer but didn’t specify when it should be utilized. Hormonerefractory prostate cancer is a continuum. In general, the first sign of disease breakthrough is a rising PSA, and the patient is often asymptomatic. Generally, after seven to 12 months, we start seeing changes in scans, and patients become symptomatic. A window exists during which markers are going up and the patient is asymptomatic, yet the patient may want treatment.

Often physicians will try a second hormonal manipulation, such as ketoconazole, high-dose bicalutamide or nilutamide. All of these seem to have a 20 percent to 40 percent rate of response and a median time to progression of about four months, but no proven survival benefit.

An interesting observation gleaned from a subanalysis of TAX-327 data is that the hazard ratios for survival are similar whether patients are asymptomatic or symptomatic, and the difference of two months in median survival is conserved for both symptomatic and asymptomatic patients.

It is difficult to decide whether to utilize docetaxel in patients who are asymptomatic but have rising PSAs. It is important to evaluate how rapidly the disease is progressing. Clearly, if the PSA is not rising rapidly, you have time to try other manipulations. In my experience, by the time those manipulations fail, patients need chemotherapy.

In asymptomatic patients with rapidly rising or rapidly doubling PSA levels, progression of soft-tissue disease or progression on bone scan, I consider initiating chemotherapy. During the initial PSA rise, unless the patient has visceral disease, I’m not in favor of using chemotherapy. I would utilize an investigational agent or a secondary hormonal manipulation.

To use a baseball analogy, docetaxel can be saved as the “relief pitcher” for late innings, or you can use it earlier as your starting pitcher. Either way, we know that docetaxel has a high response rate and a proven survival benefit.

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TAX-327: Docetaxel/prednisone versus mitoxantrone/prednisone

Prostate Cancer Update 2005 (3)

MARIO A EISENBERGER, MD: The patients enrolled in this trial had hormone-refractory metastatic prostate cancer and a testosterone level in the castrate range. Patients were allowed to have received only one prior chemotherapy treatment with estramustine and were withdrawn from anti-androgen therapy. The trial’s endpoint was survival. We wanted to detect a hazard ratio of 0.75 for survival in favor of docetaxel.

The three treatment arms included: (1) docetaxel 75 mg/m2 every three weeks plus prednisone, (2) docetaxel 30 mg/m2 weekly for five out of six weeks plus prednisone and (3) mitoxantrone 12 mg/m2 every three weeks plus prednisone. We enrolled 1,006 patients over two years, and the analysis occurred about three and a half years after the first patient was enrolled. Each treatment arm had more than 300 patients.

With a median follow-up of about 20.7 months, the median survival for patients treated with every three-week docetaxel and prednisone was 18.9 months, compared to a median survival of 16.5 months for those treated with mitoxantrone and prednisone. Forty-five percent and 48 percent of patients treated with every three-week and weekly docetaxel had a 50 percent decline in their PSA that lasted for at least three weeks, and 32 percent of the patients treated with mitoxantrone and prednisone had a 50 percent decline in their PSA, which was significantly different (p < 0.001).

About 30 percent of the patients in the docetaxel arms had a reduction in pain, compared to about 20 percent of the patients treated with mitoxantrone and prednisone. The difference in the reduction in pain between mitoxantrone plus prednisone and every three-week docetaxel plus prednisone was also significant (p = 0.01). Very few objective responses in soft tissue metastases were reported in all three arms.

The toxicity was as predicted with these compounds, mostly myelosuppression. Thirty-two percent of the patients treated with every three-week docetaxel and prednisone had myelosuppression (Grade III/IV neutropenia), but less than three percent had neutropenic fever, documented sepsis or death. Only 1.5 percent of the patients receiving weekly docetaxel and prednisone had myelosuppression (Grade III/IV neutropenia), compared to about 20 percent of the patients on mitoxantrone and prednisone. The incidence of febrile complications was very low and similar in all three treatment arms.

The other toxicities were minor (≤Grade II) and not dose limiting. There was some neuropathy, fatigue and edema in the patients treated with docetaxel, which is more toxic than mitoxantrone and prednisone, but the toxicities were quite reasonable. We had very few episodes of significant nausea and vomiting and some changes in liver function tests. Alopecia was reported more frequently with every three-week docetaxel, and changes in the nails and eyes were reported more with weekly docetaxel. About 16 percent of the patients on weekly docetaxel discontinued treatment because of an adverse drug reaction, compared to only 11 percent on every three-week docetaxel.

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Comparing the results from SWOG-S9916 to those from TAX-327

Prostate Cancer Update 2005 (3)

DR CRAWFORD: We reported at a plenary session at ASCO 2004 and published in The New England Journal of Medicine our large Phase III trial headed up by Dan Petrylak from Columbia, which compared docetaxel and estramustine to mitoxantrone and prednisone.

This was the first trial in my history in the Southwest Oncology Group to show a survival benefit, and we’ve studied every drug known to mankind. While the survival benefit in SWOG-S9916 was a couple of months, it’s a big leap. The next leap, I think, is to use that as a basis for a platform to add new agents.

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Prostate Cancer Update 2005 (3)

DR EISENBERGER: The results from those two trials are very similar. In SWOG-S9916, survival for the patients treated with docetaxel plus estramustine was 17.5 months compared to 15.6 months for those on mitoxantrone plus prednisone. A PSA response occurred in 50 percent of the patients on docetaxel plus estramustine, compared to 27 percent of those on mitoxantrone plus prednisone. The difference between the two trials was in the toxicities. Although no head-to- head comparison was conducted, estramustine plus docetaxel was more toxic than docetaxel plus prednisone. The most significant toxicities were cardiovascular or thrombotic. Halfway through SWOG-S9916, the protocol was amended to include prophylactic anticoagulation (ie, warfarin plus aspirin) for the patients treated with estramustine.

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Prostate Cancer Update 2005 (2)

DR D’AMICO: In 2004, results from two trials comparing docetaxel-containing regimens to mitoxantrone with prednisone in patients with hormone-refractory metastatic prostate cancer were published in The New England Journal of Medicine — one was SWOG-9916 by Dr Dan Petrylak, and the other was TAX-327 by Dr Ian Tannock. Both studies demonstrated a survival benefit of about two months for the docetaxelcontaining regimen.

One study combined estramustine with docetaxel, and the other evaluated docetaxel alone. Both studies showed a similar prolongation in survival, but because estramustine increased toxicity, it is not considered a necessary part of the regimen. Two dosing regimens for docetaxel were evaluated: every three weeks and weekly. The every three-week regimen appeared to be better, although the FDA and others are going to validate that in the future. The currently accepted regimen for docetaxel is 75 mg/m2 every three weeks.

Patients whose performance status is good — such as men under 65 years of age — will tolerate docetaxel well. They come in, receive the infusion, go home, have a couple of days with some symptoms and then go back to their routine.

Toxic deaths are rare and few patients require hospitalization for complications. Growth factors can be used to bring up blood counts if need be, and these patients must have their blood counts monitored. This is a new arena, not for medical oncologists, but for the urologists and radiation oncologists who deal with patients with prostate cancer.

Prostate Cancer Update 2005 (2)

DR GOMELLA: The new data showing a survival advantage with docetaxel-based chemotherapy in patients with hormonerefractory prostate cancer are provocative. The two large trials reported at ASCO in 2004 have made early chemotherapy a more viable option. The tolerability of docetaxel is also significantly better than the estramustine-based therapies that caused so much toxicity in the 1990s.

At this time, the average patient with a PSA recurrence who has not demonstrated metastatic disease is treated with hormonal therapy front line and, if that fails, another hormone intervention second line. My third-line treatment is chemotherapy, because I believe our best opportunity to intercede and have a favorable outcome is in the earliest stages of progression.

For example, we learned that salvage radiation therapy after radical prostatectomy is more effective when used earlier rather than later. We used to initiate salvage therapy when the patient’s PSA reached 4 ng/mL, then 2 ng/mL, then 1.5 ng/mL. Now, for the best outcome, we initiate salvage radiation when the PSA reaches 1 ng/mL. I believe using chemotherapy earlier in the disease is reasonable to consider, although we don’t have any good studies yet to say it should be utilized at the first evidence of PSA recurrence.

We are also seeing an emphasis on a multidisciplinary team approach and consulting with the medical oncologist earlier in the management of prostate cancer. Previously, we didn’t have effective chemotherapy regimens to offer patients — nothing demonstrated a statistically significant advantage in large prospective randomized trials until mid-2004, when the two positive docetaxel studies were reported. I believe we will see an intrinsic change in the management of this disease as a result of these data. In addition, other compounds will be available in the next couple of years that may further redefine how patients with PSA recurrence or progressive prostate cancer are managed.

Prostate Cancer Update 2005 (2)

DR DREICER: Although I was obviously delighted to see the results of SWOG-S9916 and TAX-327, in effect, they’ve created many more questions than were answered. The majority of the patients enrolled in the two trials had androgen- independent metastatic disease, and many, but not all, were symptomatic. Until those data were available, chemotherapy in a noninvestigational setting was used to palliate patients; therefore, most patients, at least theoretically, were treated when they had disease-related symptoms.

The question now is, Does the patient who has asymptomatic metastatic disease need to be treated at that time, or later? That’s a critical question to which we don’t know the answer. In my practice, for asymptomatic patients with low-volume disease, I have a discussion about what we know about the trials. As an academician, I have clinical research opportunities for some of these patients and certainly would steer them in that direction. When a patient is not interested in participating in a clinical trial, I review the data with him and try to arrive at a reasonable decision based on his individual perspective.

Prostate Cancer Update 2005 (3)

DR KLOTZ: Among patients with metastatic disease, two trials have shown a survival benefit with docetaxel. This was widely acknowledged to be a huge step forward because, up to that point, chemotherapy provided just a quality-oflife benefit. A survival benefit is a major event. Of course, the size of that benefit was somewhere around two and a half months. The trials compared docetaxel against other chemotherapy regimens. Hence, it’s definitely a significant event in the history of the management of prostate cancer.

Clearly, the standard of care is now docetaxel, and it should be offered to patients who have hormone-refractory metastatic prostate cancer. The controversy involves whether it should be offered earlier, and those studies are being conducted. If a patient has a rapidly rising PSA with hormone-refractory metastatic disease — whether he’s symptomatic or not — I think it’s reasonable to treat him with docetaxel. I use the PSA doubling time as a surrogate marker for symptomatic progression, because I know that the patient is going to have symptoms soon. If he has hormonerefractory disease without evidence of recurrence, I don’t treat him.

Docetaxel is very well tolerated, and the mortality rate from toxicity is extremely low. I have been very impressed with the favorable toxicity profile of docetaxel. I also think that elderly patients tolerate it quite well. The toxicity associated with chemotherapy is acute, while the toxicity associated with hormonal therapy is chronic, long term and insidious. Patients receive chemotherapy for a much shorter period of time, as a rule.

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