Docetaxel Combination Therapy in Prostate Cancer

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: November 7, 2005

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Presenter: Daniel Petrylak, MD
Presenter's Affiliation: Columbia University, New York, New York
Type of Session: Scientific

Background

  • SWOG 9916 compared doctaxel/estramustine to mitoxantrone/prednisone for patients with metastatic, hormone-refractory prostate cancer, and found an improvement in overall survival in the docetaxel arm (median survival 17.5 months vs. 15.6 months).
  • One of the problems with the docetaxel/estramustine combination is that it caused more toxicity than the mitoxantrone regimen; particularly nausea, deep venous thrombosis and cardiac toxicities.
  • A sister trial, TAX327, compared q 3 week docetaxel, weekly docetaxel, and q 3 week mitoxantrone, with prednisone given to all paients in all arms. Total treatment duration in all three arms was 30 weeks.
  • The patients who received q3 week docetaxel had a median survival of 18.9 months, compared to 17.3 months for weekly docetaxel and 16.4 months for the mitoxantrone arm.
  • The reduction in the risk of death for the q3 week docetaxel arm was 24%.
  • However, the q3 week docetaxel arm had higher rates of toxicity than the other 2 arms, particularly in terms of risks of neutropenia and neuro-sensory changes.
  • Quality of life data suggest that docetaxel (either weekly or q3 week) is better tolerated than mitoxantrone.
  • Unfortunately, one cannot compare the SWOG study to the TAX327 study, because different doses of docetaxel were employed, they employed different crossover patterns, and prior chemotherapy was permitted in the SWOG study but not in the TAX327 study.
  • Despite these facts, the standard of care for metastatic, hormone-refractory prostate cancer has now become docetaxel/prednisone, and this regimen is being used as the control arm for the cooperative groups.

Materials and Methods

  • The CALGB has evaluated (in phase II studies) the combination of docetaxel, bevacizumab, and estramustine given on a q3 week basis.
  • Preliminary survival data demonstrate a 23 month median survival for this regimen.
  • Common toxicities included neutropenia (53%), fatigue (19%), and febrile neutropenia (3%).
  • This data prompted the CALGB to create a trial (CALGB9040) which randomized patients to dexamethasone/docetaxel/prednisone/placebo or dexamethasone/docetaxel/prednisone/bevacizumab.
  • One of the most important prognostic factors in hormone-refractory prostate cancer is the serum level of VEGF, and the CALGB trial incorporates this concept.
  • A different spin on using anti-angiogenesis agents is using docetaxel with thalidomide compared to docetaxel alone, and this has been explored in a phase II study.
  • 51% of the patients in the docetaxel/thalidomide arm had a PSA response, compared to 37% in the thalidomide arm
  • The median survival in the docetaxel/thalidomide arm was improved over the docetaxel alone arm (25.9 months vs. 14.7 months).
  • Fatigue, hyperglycemia and nail changes were seen in both groups.

Results

  • Integrins are proteins which are vital for the process of angiogenesis based on the attachment of endothelial cells.
  • One of the most important integrins, the Alpha V Beta 3 integrin (Vitronectin) has been shown to be involved in both prostate cell attachment as well as endothelial cell attachment.
  • An antibody to this receptor, Vitxain, has been developed for patients with hormone-refractory prostate cancer.
  • A phase II trial was designed comparing vitaxin/docetaxel/prednisone/zoledronic acid to docetaxel/prednisone/zoledronic acid, and the results of this trial will hopefully be available for presentation at ASCO 2006.
  • Calcitriol has been evaluated with weekly docetaxel, and the combination of calcitriol/docetaxel has been compared to docetaxel alone (ASCENT trial).
  • The primary endpoint was PSA decline to 50% of staring value, and the calcitriol arm did appear superior to docetaxel alone.
  • Interestingly, the combination of docetaxel/calcitriol appeared to lead to fewer adverse events, particularly deep venous thrombosis and gastrointestinal symptoms.
  • Primary survival analysis did not show a difference between the arms.

Author's Conclusions

  • Docetaxel/prednisone is the standard of care for hormone-refractory prostate cancer.
  • New combinations are being evaluated; the most promising are moving forward to phase 3 trials.

Clinical/Scientific Implications

Dr. Petrylak discussed many of the pivotal trials for hormone refractory prostate cancer, and his presentation was excellent. There has been a shift in the standard of care for metastatic, hormone- refractory prostate cancer from mitoxantrone to docetaxel, and docetaxel is well tolerated. Like most areas of oncology, metastatic prostate cancer is seeing its share of targeted therapy trials, and many of them are developing significant interest amongst physicians. As further data accrues on targeted therapies given in the metastatic setting, we may see movement towards adding these compounds earlier in the game – perhaps as adjuvant therapy for high risk disease. The side effect profiles of the newer agents will likely dictate this move. This is an exciting area of oncology, and one where many new strides will hopefully continue to improve outcomes.



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