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Hormone Refractory Prostate Cancer: Current Trends and Future Directions

Introduction. Prostate Cancer (PC) is the most common cancer in the U.S. Approximately 33,000 men die secondary to prostate cancer each yearInitially, PC cell growth and proliferation is under influence of the androgen receptor (AR)Standard first-line therapy for metastatic disease includes andro

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Hormone Refractory Prostate Cancer: Current Trends and Future Directions

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    1. Hormone Refractory Prostate Cancer: Current Trends and Future Directions James C. Mosley, III, M.D. May 25, 2007

    2. Introduction Prostate Cancer (PC) is the most common cancer in the U.S. Approximately 33,000 men die secondary to prostate cancer each year Initially, PC cell growth and proliferation is under influence of the androgen receptor (AR) Standard first-line therapy for metastatic disease includes androgen ablation with ~80% of patients demonstrating response Withdrawl of the androgen stimulation causes a proportion of the cells to undergo apoptosis, while others are arrested in the G1 phase of the cell cycle Ultimately, cellular signaling changes occur in this low-androgen environment, allowing for resumed proliferation and rendering cells unresponsive to further hormonal manipulation (HRPC) Several genes and pathways are implicated in this process

    5. Current Management Options in HRPC Further Hormonal Manipulation Steroids Estrogens Established Chemotherapy Regimen Docetaxel-first line Mitoxantrone Investigational Regimen New chemo regimens Biologic therapies Supportive Care

    6. Current Chemotherapeutic Options Tannock et al. described use of Mitoxantrone plus prednisone in a 1996 randomized trial Quality of life and pain was relieved more frequently with combination therapy Overall Survival (OS) was not improved First Line Chemotherapy Docetaxel established as first line in TAX 327 and SWOG 9916 studies in 2004

    7. Current Chemotherapeutic Options Clinical trial end-points are a topic of debate RECIST criteria are difficult to use due to bony metastases Markers of surrogacy are utilized, but the definition of response is not well-established

    8. SWOG 9916 Randomized phase III trial of Docetaxel plus Estramustine compared to Mitoxantrone plus prednisone in HRPC Based off of phase II studies of docetaxel and estramustine demonstrating decrease in PSA of >50% in 68-84% of patients with median survivals of up to 23 months Primary endpoint was OS Seconday endpoints were PFS, ORR, rate of PSA response, and adverse events

    9. SWOG 9916

    10. SWOG 9916 According to ITT analysis, median survival was 17.5 mo in Docetaxel group versus 15.3 mo in Mitoxantrone group (P=0.02, HR 0.8) Median TTP was 6.3 mo in Docetaxel group versus 3.2 mo in Mitoxantrone group (P<0.001) Rate of PSA response was greater in Docetaxel than Mitoxantrone (50% vs. 27%, P<0.001) No significant difference in pain relief

    11. SWOG 9916

    12. TAX 327 Randomized Phase III trial of Docetaxel plus prednisone in 2 dosing schedules compared to Mitoxantrone plus prednisone Primary endpoint was OS Secondary endpoints were pain reduction, QOL improvement, PSA response, and ORR

    13. TAX 327

    14. TAX 327

    15. TAX 327 Overall Survival

    16. TAX 327 QOL was also significantly improved in groups receiving docetaxel Patients without pain at initiation of therapy were more likely to complete treatment Initial analysis was completed in 8/03 Follow-up survival data reported at ASCO Prostate Cancer Symposium earlier this year through 1/07 Several other analyses have utilized this database for evaluation of surrogacy markers as well as risk factor stratification/prognostic markers

    17. TAX 327 Updated Survival

    18. What Next? Docetaxel chemotherapy improves survival and improves PFS Post-hoc analysis has demonstrated greatest benefit in those with PSA decline of >30% in SWOG 9916 What happens when patients progress on Docetaxel?

    19. Satraplatin Third-generation Platinum complex that exhibits in vitro cytotoxicity comparable to cisplatin Orally available Exhibits activity in cisplatin-resistent cell lines the DNA-adducts of satraplatin are not recognized by mismatch repair mechanism that acts on cis and carboplatin Based on favorable profiles and preclinical data of activity in HRPC cell lines, phase II studies were undertaken However 2 of 3 studies were terminated prematurely when drug production was halted

    20. Phase II/III trials of Satraplatin in HRPC

    21. Satraplatin One of the first Phase III studies was the EORTC 30972 which evaulated satraplatin plus prednisone versus prednisone alone Target accrual was 350 patients, but only 50 enrolled due to production Primary endpoints included overall survival and time to pain progression Secondary endpoints included pain intensity, response rate, time to overall disease progression, ORR, duration of responses, QOL, and safety

    22. Satraplatin Analysis of enrolled patients demonstrated: Combination arm had significantly increased PSA response (33% vs 9% P=0.046) and median PFS (5.2 vs 2.5 mo P=0.023) Overall Survival was 14.9 months in Satraplatin arm versus 11.9 months in the prednisone only arm (P=0.579)

    24. Satraplatin Toxicities were low with more frequent hematologic toxicities observed in the combination arm Based on the results of the phase II studies and the EORTC study, a large Phase III trial was planned to extend the results of the EORTC study and determine the OS benefit Termed SPARC (Satraplatin and Prednisone Against Refractory Cancer)

    25. SPARC Phase III study of Satraplatin plus prednisone versus prednisone alone in HRPC previously treated Primary endpoints were Overall Survival and Progression-Free Survival Secondary Endpoints were Time to Pain Progression PFS results presented at ASCO Prostate Cancer Symposium earlier this year

    26. SPARC

    27. SPARC Progression-Free Survival

    28. SPARC Satraplatin prolongs PFS in HRPC previously treated Also prolongs PFS in patients treated with taxanes Treatment was well-tolerated with myelosuppression more common in the Satraplatin group Overall Survival data maturing

    29. Sipuleucel-T Investigational immunotherapy product designed to stimulate T-cell immunity against PAP Consists of autologous APCs cultured with a fusion protein (PA2024) of PAP linked to GM-CSF Preclinical studies in rats demonstrated that PA2024 loaded into dendritic cells can induce cellular immune responses in vivo to tumors expressing PAP Small et al. developed a Phase I/II study of the PA2024 product loaded into autologous dendritic cells (Provenge™) Initial phase I/II study demonstrated that the product was well tolerated and induced a clinical immune response in all patients treated This study also noted a trend toward delay of TTP that correlated with immune response as well as a PSA response of 50% in 10% of patients

    33. Sipuleucel-T Based on findings by Small et al., a Phase III study, D9901, was initiated comparing Sipuleucel-T to placebo Primary end-point was TTP Overall Survival was not a pre-specified end-point Trial allowed for crossover at progression if on placebo

    34. Sipuleucel-T D9901

    37. Sipuleucel-T D9901 Primary end-point was not met Previous reports have demonstrated that maximal T-cell response require 8-10 weeks to develop Progression during this time could confound TTP as an endpoint Overall survival seemed to be improved in the treated group 25.9 months versus 21.4 months (P=0.01) TAX 327 demonstrated 18.9 months versus 16.5 months Result is misleading as this was not a prespecified end-point T-cell stimulation index was 8-fold higher in Provenge versus placebo

    38. Sipuleucel-T A companion study was launched at the same time, D9902 Trial was terminated early after accrual of only 98 patients due to D9901 results Complicated by fact that this did not allow for power to detect difference in TTP or OS Utilized same schema and primary end-point as D9901 Primary end-point was once again not met

    40. D9902A Overall Survival

    41. Sipuleucel-T Safety analysis in D9901 demonstrated that treatment was well tolerated Most AE’s were grade I-II and resolved within 48 hours Updated safety analysis presented to the FDA which included patients treated on all studies demonstrated an increased (NS) rate of CVAs

    42. CVA Events

    43. Sipuleucel-T A larger Phase III trial, D9902B is currently underway with 294 patients randomized P-11 is a Phase III study investigating use of Provenge in the Androgen-dependent stage as well Provenge was presented to FDA for approval hearings 3/07. Approval was denied early 5/07 stating need for further information

    44. Future Directions What is an optimal second line treatment? When is the optimal time to initiate treatment? What about other directed therapies? Several investigational/targeted agents are in Phase I/II trials Current Phase III trials: Docetaxel/Prednisone +/- Avastin (CALGB) GVAX vs. Docetaxel/prednisone (Vital-1) GVAX + Docetaxel vs. Docetaxel/prednisone (Vital-2) Atrasentan +/- Docetaxel/Prednisone (SWOG) Calcitriol +/- Docetaxel/Prednisone (ASCENT-2) Sipuleucel-T vs. placebo (D9902B) XRP6258 + prednisone vs. Mitoxantrone + prednisone (TROPIC)

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