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2012 genitourinary con

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a clinical care option slide presentation

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  • Thank you for accessing the CCO Independent Conference Coverage of the 2012 Genitourinary Cancers Symposium from San Francisco, California. In the following slides, you will find highlights of the key studies in lymphomas from this meeting. Be sure to review the slidenotes field for each slide for insightful commentary from our expert faculty. \n
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  • CRPC, castration-resistant prostate cancer; CTC, circulating tumor cells; ECOG PS, Eastern Cooperative Oncology Group performance score; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; QoL, quality of life; SRE, skeletal-related event; STOR, soft tissue objective response.\n\nDaniel P. Petrylak, MD: \nAFFIRM was a randomized phase III study of MDV3100, a selective androgen receptor antagonist, as second-line therapy for patients with CRPC who failed docetaxel. MDV3100 is unique in that it not only antagonizes the androgen receptor but prevents translocation of the androgen receptor across the nucleus. In phase I and phase II studies MDV3100 demonstrated significant PSA declines as well as objective soft tissue responses. Of note, unlike abiraterone, management of patients receiving MDV3100 does not require corticosteroids, and I think this will lead clinicians to choose it instead of abiraterone. \nFor context, with sipuleucel-T, it is thought that steroids will abrogate the therapeutic effect so the longer steroids can be delayed, the better off the patient. Thus, the lack of need for steroids is a substantial advantage of MDV3100. The other issue which I think is really interesting is that the mechanisms of resistance of MDV3100 complement abiraterone; there is upregulation of testosterone synthesis enzymes with MDV3100 treatment and resistance. It makes sense to either give these agents sequentially or to combine them at some point in the future. \n
  • CI, confidence interval; CRPC, castration-resistant prostate cancer; HR, hazard ratio; NR, not reached; OS, overall survival.\n\nDaniel P. Petrylak, MD: \nThe most important result from AFFIRM is that overall survival was improved by approximately 5 months compared to placebo. It’s important to note that this was a true placebo—no prednisone or other chemotherapeutic agents were administered. Of note, this survival difference is larger than seen in most first-line trials. \n\nDavid I. Quinn, MD, PhD: \nImportantly, the data suggest no cross-resistance between abiraterone and MDV3100.[1,2] The mechanisms, while on the same pathway, are different, which is encouraging. Dr. Petrylak, let’s say you have a patient that’s progressing after androgen deprivation therapy with one of the luteinizing hormone–related hormone agonists, or an antagonist, but has not yet received docetaxel. How would you pick between MDV3100 and abiraterone? Which one might you pick first and for what reason?\n\nDaniel P. Petrylak, MD: \nI would go with MDV3100 first. The less corticosteroid exposure patients receive the better. \n\nDavid I. Quinn, MD, PhD: \nI would do the same. \n\nDaniel P. Petrylak, MD: \nThe fact is, when you put patients on prednisone it’s difficult to get them off of it. And, of course, steroids cause osteoporosis which is already being hastened by their androgen-deprivation therapy. If these patients start living longer than the average of 20 months that we see with docetaxel, problems with bones and bone-related issues may become more significant over time. So, the longer steroids can be avoided, the better. \n\nDavid I. Quinn, MD, PhD: \nI agree that as patients receive androgen deprivation for a longer time, the bone issues become very important. \n\nReferences\n. Richards J, Lim AC, Hay CW, et al. Interactions of abiraterone, eplerenone and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res. 2012;Mar 12:[E-pub ahead of print].\n. Efstathiou E, Titus MA, Tsavachidou D, et al. MDV3100 effects on androgen receptor (AR) signaling and bone marrow testosterone concentration modulation: A preliminary report. Program and abstracts of the 2011 American Society of Clinical Oncology Annual Meeting; June 3-7, 2011; Chicago, Illinois. Abstract 4501.\n
  • CI, confidence interval; CRPC, castration-resistant prostate cancer; CT, computed tomography; HR, hazard ratio; MRI, magnetic resonance imaging; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; STOR, soft tissue objective response.\n\nDaniel P. Petrylak, MD: \nAll the different parameters measured—PSA declines of at least 50% and 90%, objective response rates, median time to PSA progression, and radiographic PFS—favored MDV3100. \n\nDavid I. Quinn, MD, PhD: \nMDV3100 clearly represents a very important new class of agent and will be very useful for our patients. \n
  • AE, adverse event; CRPC, castration-resistant prostate cancer; LFT, liver function test; SAE, serious adverse event.\n\nDaniel P. Petrylak, MD: \nImportantly, MDV3100 is a very well tolerated drug. With regard to the 5 seizures that were experienced on the study, 2 were due to non–treatment–related brain metastases, which in the past haven’t been viewed as a significant factor in prostate cancer due to the fact that patients are living longer due to improved treatments. However, newer chemotherapies and novel agents may be a precipitating factor for the seizures in these patients. In my clinical practice I’m not terribly concerned about it, but it does need to be monitored carefully. \n\nAs oncologists, we like to treat our patients with the least toxic therapy before moving toward more toxic treatments. Of note, there is as yet no biological marker to tell us when one of these 2 drugs is better suited for an individual patient than the other. \n
  • BMFS, bone metastasis-free survival; CRPC, castration-resistant prostate cancer; OS, overall survival; PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time; q4w, every 4 weeks; SC, subcutaneous.\n\nDaniel P. Petrylak, MD: \nThis was a phase III trial comparing denosumab vs placebo, both given subcutaneously every 4 weeks, in a group of patients with no evidence of metastatic disease (ie, M0). These patients are considered castrate resistant because they had locally advanced disease, and may have received surgery or radiation therapy combined with androgen deprivation therapy, followed by a rise in PSA levels but without evidence of metastases. This is an important group of patients because we currently have no effective treatment for them. From that perspective, this trial generated much interest. However, in the last few years a series of trials in this setting have either been underpowered or have returned negative results. \n
  • BMFS, bone metastasis-free survival; CI, confidence interval; CRPC, castration-resistant prostate cancer; HR, hazard ratio; PSADT, prostate-specific antigen doubling time.\n\nDaniel P. Petrylak, MD: \nThe bone metastasis-free survival endpoint was met with a statistically significant hazard ratio of 0.85. The benefit was demonstrated across a range of PSA doubling times with a suggestion that the effect is increased in patients that have a shorter doubling time (ie, higher PSA velocity).\n
  • CI, confidence interval; CRPC, castration-resistant prostate cancer; HR, hazard ratio; OS, overall survival.\n\nDaniel P. Petrylak, MD: \nNo difference in survival was seen between the 2 arms. This is not surprising given that this is a relatively early castration-resistant group who received subsequent treatments that could dilute survival in both arms. \n\nOne of the important design differences of this trial compared to other studies that have failed in this space is that patients were allowed to be on other treatments, and PSA was ignored. This may have been the reason why we saw the striking difference in bone metastasis–free survival. It’s unfortunate that the drug was not approved for this indication. \n\nDavid I. Quinn, MD, PhD: \nIt’s interesting, that despite a 4.5-month improvement in time to bone metastasis, denosumab was rejected for this indication by the FDA’s Oncology Drug Advisory Committee (ODAC). Do you think the approximate 5% incidence of osteonecrosis of the jaw with denosumab in this study influenced that decision, or do you think it was that there was too small of a difference in time to bone metastasis?\n\nDaniel P. Petrylak, MD: \nThe osteonecrosis was one factor. Another factor is that this poor prognostic group was retrospectively derived. However, the main reason is likely that the FDA wants to see an improvement of at least 6 months. The relatively small BMFS benefit combined with the rate of osteonecrosis, which is higher than reported in other studies, probably influenced their opinion that the benefit is not worth the risk. \n
  • CPT, current procedural terminology; CRT, conformal radiation therapy; IMRT, intensity modulated radiation therapy; NCI, National Cancer Institute; PT, proton therapy; SEER, Surveillance, Epidemiology and End Res\n\nDaniel P. Petrylak, MD: \nIn this population-based study of SEER-Medicare–linked data from men with nonmetastatic prostate cancer, morbidity and disease-control outcomes were compared between IMRT, proton therapy, and conformal radiotherapy for primary prostate cancer treatment.\nults.\n
  • CRT, conformal radiation therapy; IMRT, intensity modulated radiation therapy; PT, proton therapy.\n\nDaniel P. Petrylak, MD: \nOne question regarding proton radiation therapy is whether it is more efficacious than standard radiation therapy, but this could not be determined from this retrospective study. The observation of a higher rate of bowel morbidity with proton therapy than with IMRT is important for those who consider proton therapy to have fewer side effects. It’s also hard to judge whether IMRT is superior to CRT, although in this study IMRT appears somewhat better. Of note, this was a nonrandomized study, so the data were not adjusted for Gleason score grade and other issues. \n\nDavid I. Quinn, MD, PhD: \nOne of the problems with these data is the variation in the size of sets and patient selection. However, given that proton beam therapy has been around for some years now and that it’s much more expensive than IMRT or conformal radiation therapy, results such as these need to be carefully examined. In addition, we need prospective data. My personal view is that for pediatric brain tumors and sarcomas, proton beam therapy has some great advantages, but in prostate cancer I still think the jury is out. I would like to see proton therapy evaluated in a prospective, randomized trial. \n\nDaniel P. Petrylak, MD: \nI would agree with that, and also point out that the cost issue is very important. Many centers are now building large proton beam therapy treatment facilities, so we really need well-designed randomized studies to answer this question. \n
  • ALP, alkaline phosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer; CRPC, castration-resistant prostate cancer; OS, overall survival; PSA, prostate-specific antigen; QoL, quality of life; SRE, skeletal-related event.\n\nDavid I. Quinn, MD, PhD: \nThe ALSYMPCA phase III trial evaluated injected radioisotopes (radium-223) in patients with symptomatic castration-resistant prostate cancer, at least 2 bone metastases, and who were not eligible for docetaxel. Of note, patients who are not fit for docetaxel represent approximately 40% of castration-resistant prostate cancer patients and are typically excluded from clinical trials that incorporate docetaxel. \n\nIn this study, both sets of patients were offered best standard-of-care treatment, which included a number of secondary hormonal manipulations. Patients that were receiving bisphosphonates were required to continue them; initiating bisphosphonates on this study was not allowed. \n
  • ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer; CI, confidence interval; HR, hazard ratio; OS, overall survival.\n\nDavid I. Quinn, MD, PhD: \nThe overall survival data from the first interim analysis demonstrated a significant advantage for treatment with radium-223 over placebo: a difference of 2.8 months and an impressive hazard ratio of 0.695. Therefore, this may be the first in a new class of agents with a potentially significant overall survival advantage in a group of patients we have traditionally had difficulty treating. \n
  • ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer; CI, confidence interval; HR, hazard ratio; SRE, skeletal-related event.\n\nDavid I. Quinn, MD, PhD: \nThe median time to the initial SRE was significantly longer with radium-223 vs placebo. Skeletal-related events included intervention with external beam radiation therapy, the advent of spinal cord compression, pathological bone fracture, and a surgical intervention. From that perspective, there was an advantage to the radium-223 in external beam radiation, cord compression, and path fracture, but not in surgical intervention. However, although the numbers were small, the results were statistically significant in terms of a reduction in time to SRE (a 5-month difference between the curves). \n
  • AE, adverse event; ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer.\n\nDavid I. Quinn, MD, PhD: \nThe toxicity profile of radium-223 was impressive—other radiopharmaceuticals such as samarium and strontium have serious risks of hematologic toxicity. In the comparison between grades 3 and 4 adverse events there were only minimal differences between the placebo and radium-223. The lower level of bone pain in the patients that received radium-223 was expected in this well-powered study. Overall, radium-223 appears to be very well tolerated. \nIn this study, radium-223 was used as an alternative to docetaxel in unfit patients. Results are consistent with the Anderson data from several years ago that showed that strontium could produce an overall survival advantage when given with chemotherapy but with less myelosuppression, and I think this is going to be attractive from that point of view. \n\nThe logistics and delivery of a new therapy can be challenging. Radium-223 is going to be given predominantly by nuclear-medical physicians, and in some states the legal bandwidth of radio isotopes does not extend to 223 and, therefore, there will need to be regulatory alterations. I will be interested to see what the FDA thinks of this study’s definition of skeletal-related events given that it’s different from that used in studies of zoledronic acid and denosumab. Dr. Petrylak, what are your thoughts?\n\nDaniel P. Petrylak, MD: \nOne interesting finding from this trial is that it may be the first study to demonstrate a difference in epidural spinal cord metastases, which is an important finding in terms of patient morbidity. An important question is how to combine radioisotopes with other agents, such as chemotherapies. Phase I data have suggested that it is feasible to use full doses of both drug classes. Certainly, combining radium-223 with MDV3100 or with abiraterone theoretically should have no added side-effects, but a phase I study is required to prove it. \n\nI can see 2 different scenarios for radium-223: giving it up front before chemotherapy, or after chemotherapy in a very symptomatic patient. \n\nDavid I. Quinn, MD, PhD: \nIt’s interesting that we now have therapeutics with different mechanisms of action, which creates a challenge in terms of choosing combinations and sequences. \n
  • ECOG PS, Eastern Cooperative Oncology Group performance score; mCRPC, metastatic castration-resistant prostate cancer; XRT, radiotherapy. \n\nDaniel P. Petrylak, MD: \nThis phase I/II trial evaluated ipilimumab plus radiotherapy in 71 patients with progressive, metastatic CRPC who had received antiandrogen therapy and either no docetaxel or only 1 previous docetaxel-based treatment. The initial dose of ipilimumab was increased for responding patients. The primary endpoints were safety and response. \n
  • AE, adverse event; DLT, dose-limiting toxicity; HRT, hormone replacement therapy; mCRPC, metastatic castration-resistant prostate cancer; XRT, radiotherapy. \n\nDavid I. Quinn, MD, PhD: \nMost treatment-related adverse events in this study were mild (grade 1/2) and no dose-limiting toxicities were seen. However, rare but serious ipiliumab-related side effects can occur, including colitis, which in severe cases can require colectomy, and panhypopituitarism. These can be difficult to manage and can be life threatening. Importantly, such striking side effects were not seen in this trial.\n
  • CR, complete response; HRT, hormone replacement therapy; mCRPC, metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen; SD, stable disease; XRT, radiotherapy. \n\nDavid I. Quinn, MD, PhD: \nThese interesting data continue to validate the role of immunotherapy in prostate cancer, following the initial proof of principle by sipuleucel-T. Currently, phase III studies are examining ipilimumab in combination with radiotherapy, either prior to docetaxel or after docetaxel, to try and induce a release of antigens and thereby induce an immune response.[1] What’s striking about ipilimumab therapy in the setting of prostate cancer, and also in melanoma (where it’s approved), is that it can produce marked complete responses. Although these were not particularly common, they are very dramatic and a real game-changer in this setting. \n\nReference\n1. ClinicalTrials.gov. A randomized, double-blind, phase 3 trial comparing ipilimumab vs. placebo following radiotherapy in subjects with castration resistant prostate cancer that have received prior treatment with docetaxel. Available at http://clinicaltrials.gov/ct2/show/NCT00861614. Accessed March 27, 2012.\n
  • BID, twice daily; CRPC, castration-resistant prostate cancer; ECOG PS, Eastern Cooperative Oncology Group performance score; mCRPC, metastatic castration-resistant prostate cancer; MP, mitoxantrone/prednisone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; PO, orally; Q3W, every 3 weeks; QW, once weekly.\n\nDavid I. Quinn, MD, PhD: \nIn this randomized study, patients with metastatic CRPC and progression during or shortly after docetaxel were randomized to MP plus either cixutumumab or ramucirumab. Cixutumumab is a monoclonal antibody that targets IGF-1R, while ramucirumab targets VEGF receptor 2. \n
  • AE, adverse event; CIX, cixutumumab; CRPC, castration-resistant prostate cancer; G, grade; mCRPC, metastatic castration-resistant prostate cancer; MP, mitoxantrone/prednisone; PD, progressive disease; RAM, ramucirumab; WBC, white blood cells.\n\nDavid I. Quinn, MD, PhD: \nResults showed that cixutumumab and ramucirumab were well tolerated in this population, with a low rate of grade 3/4 nonhematologic adverse events.\n
  • AE, adverse event; CIX, cixutumumab; G, grade; CHF, congestive heart failure; LVEF, left ventricular ejection fraction; mCRPC, metastatic castration-resistant prostate cancer; MP, mitoxantrone/prednisone; PD, progressive disease; RAM, ramucirumab.\n\nDavid I. Quinn, MD, PhD: \nMitoxantrone and ramucirumab is an interesting combination that appears to have some activity but exacerbates left-ventricular cardiac dysfunction, which is a known toxicity of mitoxantrone. It may be possible to characterize the circulating microenvironment in serum and circulating cells to determine which patients might respond to one or other of these antibodies, particularly ramucirumab. We have seen activity previously with both sunitinib and sorafenib, which both inhibit VEGF signaling, in prostate cancer. \n\nThus, although the target of VEGF receptor 2 may be worthwhile, it was difficult to interpret responses with these other drugs because the PSA level increased while bone lesions appeared or improved. From that perspective, I think there are unanswered questions with regard to VEGF receptor 2 and what happened to bone metastases in the study, particularly in light of upcoming trials of the VEGF receptor 2 inhibitor cabozantinib. (Of note, cabozantinib also inhibits Met.) Dr. Petrylak, what are your thoughts on this?\n\nDaniel P. Petrylak, MD: \nThere has been a lot of excitement about the VEGF receptor 2 inhibitors in the setting of prostate cancer. Ramucirumab is being studied in bladder cancer where drugs such as bevacizumab and lenalidomide, which has punitive anti-antigenic activity, have failed in randomized trials. Because VEGF receptor 2 is even more specific to both tumor and endothelial cells this may distinguish this from the other VEGF-directed antibodies. It is possible that there is more endothelial damage with both cixutumumab and ramucirumab, and that’s what’s causing the effect with mitoxantrone. \n
  • cPFS, composite progression-free survival; mCRPC, metastatic castration-resistant prostate cancer; MP, mitoxantrone/prednisone; OS, overall survival; PD, progressive disease.\n\nDavid I. Quinn, MD, PhD: \nEfficacy data showed reasonable disease control with either regimen, and the study met its primary endpoint of composite PFS. Of note, sustained disease control was observed in patients in both treatment arms.\n
  • BID, twice daily; CTC, circulating tumor cell; mCRPC, metastatic castration-resistant prostate cancer; PD, progressive disease; PFS, progression-free survival; PSA, prostate-specific antigen; PO, orally; TTP, time to progression.\n\nDaniel P. Petrylak, MD: \nIn this study, patients with progressive mCRPC who had not been treated for metastatic disease were randomized to a novel antisense oligonucleotide, OGX-427 plus prednisone or prednisone alone. OGX-427 is an inhibitor of HSP27 gene expression; this is an important gene for prostate cancer because the HSP27 protein has been shown to be upregulated and correlated with resistance to hormones, chemotherapy, and radiation therapy. Extensive preclinical data with OGX-427 in radical prostatectomy patients have provided conclusive evidence that this antisense compound does hit the target and cause downregulation of the protein. This has been a problem with antisense therapies in the past. \n\nA previous randomized phase II trial evaluated the combination of OGX-427 with docetaxel and prednisone in patients with metastatic CRPC and showed an OS benefit, but no PFS improvement.[1] This phase II trial evaluated OGX-427 with prednisone alone in the same population. \n\nReference\n1. Chi KN, Hotte SJ, Yu E, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:4247-4254.\n
  • CI, confidence interval; CTC, circulating tumor cell; mCRPC, metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen.\n\nDaniel P. Petrylak, MD: \nResults showed a clear difference in PSA responses and no disease progression in nearly three quarters of OGX-427–treated patients vs only about one third of patients who received only prednisone. All the PSA levels that were evaluated showed measurable disease responses to this compound and, importantly, there were conversions of circulating tumor cells. One half of the patients receiving OGX-427 and prednisone converted from more than 5 CTCs per 7.3 mL to fewer than 5 CTCs per 7.3 mL. \n\nDavid I. Quinn, MD, PhD: \nI think HSP27 going to be an important target and hopefully we’ll see some more data with this agent soon. \n
  • ALT, alanine aminotransferase; AST, aspartate aminotransferase; mCRPC, metastatic castration-resistant prostate cancer.\n\nDavid I. Quinn, MD, PhD: \nToxicities were tolerable in this study, with few patients experiencing grade 3/4 adverse treatment-related events.\n
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  • CBR, clinical benefit rate; DC, dendritic cell; ECOG PS, Eastern Cooperative Oncology Group performance score; mRCC, metastatic renal cell carcinoma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors.\n\nDavid I. Quinn, MD, PhD: \nIn this phase II study, patients with newly diagnosed, advanced RCC received sunitinib plus a novel dendritic cell vaccine, AGS-003. Sunitinib is the most frequently used first-line VEGF tyrosine kinase inhibitor in the setting of RCC. AGS-003 is a personalized immunotherapy that involves the administration of autologous RNA-loaded dendritic cells to stimulate cytotoxic T-cell proliferation. In this phase II study, patients were selected who had not yet had a nephrectomy. Following removal of the neoplastic kidney and leukapheresis to collect dendritic cells, patient tumor cell RNA was used to stimulate the dendritic cells to produce, in effect, a personalized vaccine. The patients were then started on sunitinib followed by infusion of their own RNA-loaded dendritic cells. \n
  • CBR, clinical benefit rate; mRCC, metastatic renal cell carcinoma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.\n\nDavid I. Quinn, MD, PhD: \nEfficacy results showed a nearly 40% response rate, with stable disease in another 24%, and a median PFS of nearly 1 year. With regard to the 3 patients who achieved a partial response after a prolonged booster phase (ie, AGS-003 every 3 months) it was unusual that it developed relatively late. The median PFS of 11.2 months is similar to what we see with sunitinib alone. Overall, it appears this immunotherapy can be safely combined with sunitinib and appears to induce an immune response. The question of whether the combination of AGS-003 and sunitinib may be better than sunitinib alone needs to be answered in a phase III trial. Dr. Petrylak, what is your perspective on these data?\n\nDaniel P. Petrylak, MD: \nThere have been a number of attempts to combine targeted therapy with immunotherapy which have not been successful and have been marred by toxicity. The late responses, which as you pointed out are not often seen with sunitinib, imply that there is an active immune mechanism. I agree on the need for a randomized trial—there have been many situations of drugs for RCC with positive phase II data that did not pan out in further testing. So, I think these are exciting data. \n
  • AE, adverse event; mRCC, metastatic renal cell carcinoma; RCC, renal cell carcinoma.\n\nDavid I. Quinn, MD, PhD: \nSafety results showed that AGS-003 was well tolerated, and no immunotherapy-related serious adverse events or grade 3/4 adverse events were seen.\n
  • ECOG PS, Eastern Cooperative Oncology Group performance score; ORR, overall response rate; OS, overall survival; PD, pharmacodynamics; PFS, progression-free survival; PK, pharmacokinetics; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors.\n\nDaniel P. Petrylak, MD: \nThe phase II MET111644 trial evaluated the MET inhibitor foretinib in patints with papillary RCC, using either intermittent treatment or daily therapy. MET expression has been a target of interest in the setting of papillary renal cell carcinoma as these patients tend not to respond well to immune therapy or to growth factor therapies. \n
  • DOR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; PR, partial response; \nSD, stable disease.\n\nDaniel P. Petrylak, MD: \nThe responses to foretinib were similar with both the daily dosing and intermittent dosing, which was disappointing as neither strategy was shown to be significantly better than results from retrospective studies in patients with non–clear cell RCC variants. But, of course, this was not a randomized trial. \n\nDavid I. Quinn, MD, PhD: \nIt will be interesting to see what the median overall survival is in this group. I think it’s helpful that they have examined foretinib in this particular RCC subtype, which is the second most common after clear-cell carcinoma. \n
  • ALT, alanine aminotransferase; AST, aspartate aminotransferase.\n\nDaniel P. Petrylak, MD: \nForetinib is a very well tolerated drug. Also, few other studies in RCC have evaluated this patient subtype, so these are valuable data. \n
  • BID, twice daily; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance score; HR, hazard ratio; IFN-α, interferon alpha; mRCC, metastatic renal cell carcinoma; PFS, progression-free survival; mRCC, metastatic renal cell carcinoma.\n\nDavid I. Quinn, MD, PhD: \nThe AXIS study compared axitinib vs sorafenib in patients with progressive, metastatic RCC who had failed 1 previous systemic first-line regimen. The results, showing a significant improvement in PFS with axitinib, resulted in approval in the United States by the FDA for use in patients with metastatic RCC who have relapsed after 1 line of therapy. \n
  • BID, twice daily.\n\nDavid I. Quinn, MD, PhD: \nIn the AXIS study, about one quarter of patients required a dose reduction for toxicity, which was generally not hypertension; we treat the hypertension and leave the patient on the drugs, which results in some side effects consistent with other drugs in its class. No dose change occurred in 39% of patients. Patients that had not developed hypertension or did not have a significant level of toxicity were permitted to dose escalate. The issue is: Does dose escalation improve outcomes? \n\nThere is a precedent with this group of drugs where, if a patient develops hypertension (generally considered a diastolic blood pressure consistently above 90 mmHg), their outcome is better in terms of both PFS and OS. The question is whether hypertension is a biomarker indicating adequate exposure to the drug; the purpose of this analysis was to examine those titration data and to assess the duration of disease control and response with first-line axitinib. \n
  • AE, adverse event; BID, twice daily; CI, confidence interval; NR, not reached; PFS, progression-free survival.\n\nDavid I. Quinn, MD, PhD: \nThe PFS curves with dose-escalated and non–dose-escalated axitinib were superior to sorafenib. The PFS benefit to escalating axitinib appeared to be most significant for patients that continued on treatment for more than 9 months. This demonstrates that dose escalation of axitinib is feasible. Of note, decreased toxicities in dose-titrated patients included hypertension; it is possible that it is not a biomarker of response for some patients. There also was less hypothyroidism. This suggests that this group of patients, who did not develop hypertension or other toxicities, were candidates for dose escalation but had something biologically different about them that affected their response to these drugs. The issue of dose escalation needs to be looked at prospectively. \n\nAn ongoing prospective phase II study of first-line axitinib in RCC will eventually randomize approximately 200 patients without hypertension or other toxicity to dose escalation—similar to what the AXIS study—or to continue on the same dose.[1] These data should help determine whether axitinib should be dose escalated or whether 5-mg twice a day is appropriate for all patients.\n\nReference\n1. ClinicalTrials.gov. Randomized, double-blind phase 2 study of axitinib (AG-013736) with or without dose titration in patients with metastatic renal cell carcinoma. Available at: http://clinicaltrials.gov/ct2/show/NCT00835978. Accessed April 18, 2012\n
  • CI, confidence interval; mPFS, median progression-free survival; NR, not reached; PFS, progression-free survival.\n\nDavid I. Quinn, MD, PhD: \nRini and colleagues also looked at whether a response to either axitinib or sorafenib in the AXIS study was predicted by prior response to sunitinib. The bottom line was that it appeared that patients who continued on sorafenib beyond 6 months may do better based on their prior response to sunitinib. By contrast, there was no difference in axitinib-treated patients based on prior response to sunitinib. This underlines that despite similarities of these drugs that could predict subsequent response, essentially, response cannot be predicted for a patient going from sunitinib to subsequent axitinib. \n\nAdditionally, there were some radical responses to sorafenib that didn’t seem to be predicted by prior duration of sunitinib. From that perspective, this is an interesting iteration of data from the AXIS study. I don’t think it provides therapeutically relevant data at this time, but the data are starting to inform us about the biology of these agents. What do you think, Dr. Petrylak?\n\nDaniel P. Petrylak, MD: \nThe difficulty in predicting responses is one of the most important observations from AXIS. With this phenomenon of patients responding to multiple tyrosine kinase inhibitors, it’s difficult to develop a treatment algorithm that incorporates third- and fourth-line therapy. This study provides more justification for trying these drugs in a sequential fashion. \n
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  • AJCC, American Joint Committee on Cancer; CT, computed tomography; MSCV, mediastinal/supraclavicular; PA, para-aortic; RT, radiation therapy.\n\nDaniel P. Petrylak, MD: \nRadiation therapy is an option for patients with testicular seminoma, in addition to observation. This retrospective study evaluated data on long-term outcomes with radiotherapy in patients with stage II testicular seminoma treated between 1974 and 2007. Some physicians use high-dose carboplatin in this population, but in my opinion, the jury is still out on whether that is beneficial. \n
  • CSS, cause-specific survival; KM, Kaplan-Meier; MCE, major cardiac event; MSCV, mediastinal/supraclavicular; OS, overall survival; PA, para-aortic; RT, radiation therapy; SM, second malignancy.\n\nDaniel P. Petrylak, MD: \nIn this study, the relapse-free survival estimates showed that relapse was stage dependent and associated with intra-diaphragmatic RT alone, particularly for patients with stage IIb disease. The real issue is the lack of durable responses. When these patients relapse they can relapse distally. Second malignancies are an issue as well, and develop in approximately 5% of patients. \n\nDavid I. Quinn, MD, PhD: \nIt is interesting that for stage II seminoma, with involvement of retroperitoneal lymph nodes, many medical oncologists have moved away from using radiation. These data confirm that a patient with low-volume disease can do very well with radiation, with the caveats of the issues of secondary malignancies and cardiac arrest. However, those are issues with chemotherapy as well. \n\nIn patients with stage I seminoma, we have no follow-up data for carboplatin beyond 7-8 years and thus do not know whether there are issues related to cardiovascular health and secondary malignancy in that group of patients.\n
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  • BCG, Bacillus Calmette-Guerin; NMIBC, nonmuscle-invasive bladder cancer; SNP, single nucleotide polymorphism.\n\nDavid I. Quinn, MD, PhD: \nIn this study of single nucleotide polymorphisms associated with BCG response in patients with bladder cancer, the investigators looked not only at the tumor but also at the patient’s own genetic make-up. Both of SNPs evaluated in this study (BCL2L1 and TACC3) had been postulated in other, smaller studies to be associated with BCG outcomes. Importantly, in this study these SNPs were validated in an independent cohort of 168 patients that had been treated with BCG in the same manner. \n
  • BCG, Bacillus Calmette-Guerin; CI, confidence interval; NMIBC, non-muscle invasive bladder cancer; OR, odds ratio; SNP, single nucleotide polymorphism.\n\nDavid I. Quinn, MD, PhD: \nResults showed that the SNPs TACC3 and BCL2L1 correlated with response and maintenance of a disease-free state after BCG in patients with bladder cancer. This effect was seen in both cohorts; found in the first cohort and confirmed in the validation cohort. \n\nOf note, there were 12 SNPs that were not validated for BCG response across the 2 cohorts, but were investigated for other associations. Results showed that a SNP for ERCC1, a nuclear-excision repair pathway molecule, was associated with persistence of disease. This had not been previously documented for this particular SNP. From that perspective, we are now getting to a point where we may be able to define patients that can do well with BCG and those that are unlikely to do well, based on SNPs. It would be nice to be able to predict a complete response from BCG and, for those patients that are unlikely to be complete responders or do not achieve a complete response on their first round of BCG therapy, to move them on to a more definitive therapy, either a cystectomy or chemoradiation. \n\nThe discovery that the ERCC1 polymorphism predicts persistence of disease is very important and raises a question: We have assumed that BCG therapy works through immune-stimulation but, in fact ,it may have other effects in terms of DNA repair that are as yet not understood. For a common therapy for superficial bladder cancer, these data underline that our understanding remains somewhat rudimentary. \n\nDaniel P. Petrylak, MD: \nI agree. The surprising finding about the ERCC1 SNP is interesting because, as you pointed out, we don’t know the exact mechanism by which BCG works. In some studies, ERCC1 has been correlated with resistance to gemcitabine/cisplatin, so this may be more of a common mechanism for both the superficial and metastatic states of disease. Certainly, understanding this may help design more rational approaches for patients with non-muscle-invasive bladder cancer who need better therapy. It is important to note that superficial bladder cancer is one of the most prevalent tumors and accounts for a huge amount of healthcare costs. \n
  • CMT, combined-modality therapy; DSS, disease-specific survival; MIBC, muscle-invasive bladder cancer; OS, overall survival; RTOG, Radiation Therapy Oncology Group.\n\nDaniel P. Petrylak, MD: \nMak and colleagues conducted a pooled analysis of RTOG studies of combined-modality therapy in patients with muscle-invasive bladder cancer. Usually, combined modality therapy involves chemotherapy plus radiation in patients who did not achieve a complete response. \n
  • CMT, combined-modality therapy; DSS, disease-specific survival; MIBC, muscle-invasive bladder cancer; OS, overall survival.\n\nDaniel P. Petrylak, MD: \nIn this pooled analysis of CMT in bladder cancer, decreased overall disease-specific survival was, not surprisingly, associated with a higher clinical stage. This is similar to observations from other bladder cancer studies of an association with stage and a complete response to combined modality therapy. The long-term outcomes were comparable to reports from single-institution studies. I think, especially for elderly patients, this opens up a new treatment modality that should be considered for patients with bladder cancer. \n\nDavid I. Quinn, MD, PhD: \nI think we’re probably under-using CMT; we’re probably pushing borderline patients with renal impairments and poor performance to cystectomy rather than giving them chemoradiation. Of course, a big factor is cisplatin. Data from the UK BC2001 study[1] demonstrated that using the anal cancer regimen—mitomycin-C plus 5-fluorouracil—with radiation for patients with muscle-invasive bladder cancer and a glomerular filtration rate as low as 25 mL per minute produces significant improvements in loco-regional disease-free survival that are similar to the Massachusetts General / RTOG experience that has been predicated on cisplatin.[2] I expect that more mature BC2001 study results will be presented at the ASCO 2012 annual meeting and may demonstrate that this is a regimen that can be given to older people with renal impairment, which would change clinical practice. The RTOG is working on repeating this study in the United States and will include analysis of potential biomarkers for response to radiation. \n\nDaniel P. Petrylak, MD: \nThe 2-year mortality rate for elderly patients with bladder cancer is surprisingly high, around 50% in my experience. This highlights the need to improve treatment of elderly patients, and these results showing that similar OS rates with CMT as with cystectomy-based strategies are an important observation.\n\nReferences\n1. James ND, Hussain SA, Hall E, et al. Results of a phase III randomized trial of synchronous chemoradiotherapy (CRT) compared to radiotherapy (RT) alone in muscle-invasive bladder cancer (MIBC) (BC2001 CRUK/01/004). Program and abstracts of the 2010 Annual Meeting of the American Society of Clinical Oncology; June 4-8, 2010; Chicago, Illinois. Abstract 4517.\n\n2. Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol. 2012;61:705-711.\n
  • DD-MVAC, dose dense methotrexate, vinblastine, doxorubicin, and cisplatin; DSS, disease-specific survival; OS, overall survival.\n\nDavid I. Quinn, MD, PhD: \nIn this phase II study, patients with bladder cancer or upper track tumors received a high-dose-intensity regimen of MVAC, developed by Sternberg and colleagues, with growth factors for support. The reason surgery was delayed at least 6 weeks after the last dose of bevacizumab due to prior experience with increased surgical complications (eg, delays in wound healing[1,2]) when surgery is done soon after bevacizumab. \n \nReferences\nJonasch E, Wood CG, Matin SF, et al. Phase II presurgical feasibility study of bevacizumab in untreated patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:4076-4081.\n\n2. Sehouli J, Papanikolaou G, Braicu El, et al. Feasibility of surgery after systemic treatment with the humanized recombinant antibody bevacizumab in heavily pretreated patients with advanced epithelial ovarian cancer. Ann Surg Oncol. 2012;19:1326-1333.\n \n
  • DD-MVAC, dose dense methotrexate, vinblastine, doxorubicin, and cisplatin; DSS, disease-specific survival; Med, median; NR, not reached; OS, overall survival.\n\nDavid I. Quinn, MD, PhD: \nResults show very good overall and disease-specific survival and, although there were only a small number of upper-tract patients, they seemed to do very well, with few relapses or deaths. This supports a growing opinion that upper-tract tumors can be effectively treated with peri-operative chemotherapy, ideally given before nephroureterectomy, helping to preserve as much renal function as possible. \n\nOf note, the patients that still had significant disease at the end of neoadjuvant therapy did extremely poorly; those with residual T3 or T4 disease have a very high mortality risk from their disease. As the field is moving toward neoadjuvant therapy, it’s important to note that for patients with an incomplete response there is no evidence to support giving them neoadjuvant therapy and their survival is very poor. This is an area where more clinical trials are needed, and more enrollment in existing trials. \n\nDaniel P. Petrylak, MD: \nThere are some very interesting points about this study. The pathological response rate was very similar to the rate with MVAC in the SWOG 8710 trial[1]; about 38% of patients down-staged to pT0. However, in this study, patients received 4 cycles whereas, in the SWOG study, only 3 cycles were administered. \n\nReference\n1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349;859-866.\n
  • DD-MVAC, dose dense methotrexate, vinblastine, doxorubicin, and cisplatin.\n\nDavid I. Quinn, MD, PhD: \nThe combination of DD-MVAC and bevacizumab was tolerated very well. Importantly, there was only a 4% rate of neutropenic fever—those of us who went through the era of using standard MVAC are aware that neutropenic fever was a considerable problem. \n\nDaniel P. Petrylak, MD: \nOne of the more interesting things that is not seen here is that there were no reported vascular events related to the chemotherapy, nor were there any vascular events associated with cystectomy. This is important because high rates of deep vein thrombosis have been seen in studies of gemcitabine plus bevacizumab, and in about 15% of patients treated with classic MVAC. But it was not seen in this study, which could be due to a variety of factors such as being a single-institution study or selection bias. A randomized trial is needed to answer this question. \n\nDavid I. Quinn, MD, PhD: \nIt’s a good point about the lack of thromboembolic phenomenon here, and although that may be a particular center effect, it’s something that we do need to consider in expanding this approach. \n
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    • 1. Genitourinary Cancers CCO Independent Conference Coverage of the 2012 Genitourinary Cancers Symposium* February 2-4, 2012 San Francisco, California *CCO is an independent medical education company that provides state-of-the-art information to healthcare *CCO is an independent medical education company that provides state-of-the-art medical information and other professionals through conference coverage to healthcare educational programs. professionals through conference coverage and other educational programs.This program is supported by educational grants from
    • 2. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (e-mail permissions@clinicaloptions.com)DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of theCCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providingeducational grants. The materials may discuss uses and dosages for therapeutic products that have notbeen approved by the United States Food and Drug Administration. A qualified healthcare professionalshould be consulted before using any therapeutic product discussed. Readers should verify all informationand data before treating patients or using any therapies described in these materials.
    • 3. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Faculty Daniel P. Petrylak, MD Professor of Medicine Columbia University Medical Center Herbert Irving Cancer Center New York, New York David I. Quinn, MD, PhD Associate Professor of Medicine Division of Cancer Medicine and Blood Diseases The University of Southern California Medical Director, USC Norris Cancer Hospital and Clinics Los Angeles, California
    • 4. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Faculty Disclosures Daniel P. Petrylak, MD, has disclosed that he has participated on advisory boards or as a consultant for Amgen, AstraZeneca, Bellicum, Dendreon, Egenix, Ferring, Johnson & Johnson, Millennium, Novartis, and Otsuka; has received research support from Abbott, Boehringer Ingelheim, Celgene, Dendreon, Eisai, GlaxoSmithKline, Johnson & Johnson, Medivation, Pfizer, Progenics, and sanofi-aventis, and has served as a board member on the Prostate Conditions Education Council. David I. Quinn, MD, PhD, has disclosed that he has received consulting fees from AVEO, Bayer, Dendreon, Medivation, Novartis, Onyx, and Pfizer.
    • 5. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Overview  Prostate cancer  Renal cell carcinoma  Testicular cancer  Urothelial cancer
    • 6. Prostate Cancer
    • 7. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AFFIRM: Phase III Trial of MDV3100 in Post-Docetaxel CRPC Study stopped at planned interim analysis at 520 events with observation of statistically significant, clinically meaningful OS benefit Randomized 2:1 MDV3100 160 mg/day (n = 800) Patients with progressive CRPC who failed docetaxel Stratified by ECOG PS and Mean Brief Pain chemotherapy Inventory question 3 score (N = 1199) Placebo (n = 399)  Primary endpoint: OS  Secondary endpoints: – Response: PSA response, STOR, QoL, pain palliation, CTC – Progression: radiographic PFS, time to PSA progression, time to first SREScher HI, et al. ASCO GU 2012. Abstract LBA1.
    • 8. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AFFIRM Trial of MDV3100 in Post- Docetaxel CRPC: OS  OS improved with MDV3100 vs placebo  Median follow-up: 14.4 mos HR: 0.631 (95% CI: 0.529-0.752; P < .0001) 100 37% reduction in risk of death 90 80 MDV3100: 18.4 mos 70 (95% CI: 17.3-NR) Survival (%) 60 50 40 30 20 Placebo: 13.6 mos (95% CI: 11.3-15.8) 10 0 0 3 6 9 12 15 18 21 24 Duration of OS (Mos) MOV3100 800 775 701 627 400 211 72 7 0 Placebo 399 376 317 263 167 81 33 3 0Scher HI, et al. ASCO GU 2012. Abstract LBA1.
    • 9. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AFFIRM Trial of MDV3100 in Post- Docetaxel CRPC: Secondary Outcomes  Secondary outcomes support survival benefit Response, % MDV3100 Placebo P Value (n = 800) (n = 399) PSA decline  ≥ 50% from baseline 54.0 1.5 < .0001  ≥ 90% from baseline 24.8 0.9 < .0001 STOR by CT/MRI 28.9 3.8 < .0001 Progression, Mos MDV3100 Placebo HR (n = 800) (n = 399) (95% CI; P Value) Median time to PSA 8.3 3.0 0.0248 progression (0.204-0.303; < .0001) Median radiographic PFS 8.3 2.9 0.404 (0.350-0.466; < .0001)Scher HI, et al. ASCO GU 2012. Abstract LBA1.
    • 10. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AFFIRM Trial of MDV3100 in Post- Docetaxel CRPC: Toxicity  Adverse event rates similar for MDV3100 and placebo, despite longer reporting period for MDV3100  No on-treatment patient deaths Treatment-Related AEs, % All Grades Grade ≥ 3 Events MDV3100 Placebo MDV3100 Placebo (n = 800) (n = 399) (n = 800) (n = 399) All AEs 98.1 97.7 45.3 53.1 All serious AEs 33.5 38.6 28.4 33.6 Fatigue 33.6 29.1 6.3 7.3 Cardiac disorders 6.1 7.5 0.9 2.0  Myocardial infarction 0.3 0.5 0.3 0.5 LFT abnormalities 1.0 1.5 0.4 0.8 Seizure* 0.6 0 0.6 0 *2 of 5 patients experiencing seizure on MDV3100 were found to have brain metastases; 1 was receiving IV lidocaine for biopsy.Scher HI, et al. ASCO GU 2012. Abstract LBA1.
    • 11. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Phase III Study: BMFS With Denosumab in M0 CRPC With Aggressive PSA Kinetics Bone metastasis or death Double-blind randomization Denosumab 120 mg SC q4w Patients with M0 (n = 716) CRPC at high risk for bone metastases: PSA ≥ 8.0 ng/mL Calcium and vitamin D Survival or PSADT ≤ 10.0 mos supplementation Follow-up (N = 1432) Off investigational Placebo 120 mg SC q4w product (n = 716)  Primary endpoint: bone metastasis-free survival  Secondary endpoints: time to first bone metastasis (either symptomatic or asymptomatic), OSSmith MR, et al. ASCO GU 2012. Abstract 6. Smith MR, et al. Lancet. 2012;379:39-46.
    • 12. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Denosumab in High-Risk M0 CRPC: Bone Metastasis–Free Survival  Median BMFS prolonged with denosumab – Denosumab: 29.5 mos – Placebo: 25.2 mos – HR: 0.85 (95% CI: 0.73-0.98; P = .028)  Robust treatment effect demonstrated in men identified as high-risk by short PSADT Median BMFS Denosumab, Mos Placebo, Mos HR (95% CI) P Value PSADT ≤ 4 mos 25.8 18.3 0.71 (0.56-0.90) .004 PSADT ≤ 6 mos 25.9 18.7 0.77 (0.64-0.93) .006 PSADT ≤ 10 mos 28.4 22.4 0.84 (0.72-0.99) .042Smith MR, et al. ASCO GU 2012. Abstract 6.
    • 13. 2012 Genitourinary Cancers Symposium: Highlights clinicaloptions.com/oncology Denosumab in High-Risk M0 CRPC: Secondary Endpoints  OS: no improvement with denosumab  Time to first bone metastasis prolonged vs placebo with denosumab vs placebo  Fewer symptomatic bone metastases with denosumab vs placebo Overall Survival Time to Symptomatic Bone MetastasisProportion of Patients Proportion of Patients 1.0 1.0 Without Symptomatic Bone Metastases 0.8 0.8 HR: 0.67 (95% CI: 0.49-0.92) Survived 0.6 0.6 P = .013 HR: 1.01 (95% CI: 0.85-1.20) Risk Reduction 33% 0.4 P = .91 0.4 Events, n (%) 0.2 Placebo 0.2 Placebo 96 (13) Denosumab Denosumab 69 (10) 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 Study Month Study Month Smith MR, et al. ASCO GU 2012. Abstract 6. Smith MR et al, Lancet. 2012;379:39-46.
    • 14. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology CRT vs IMRT vs Proton Therapy for Localized Prostate Cancer  Comparison of morbidity and disease control between conformal radiation therapy, intensity modulated RT, and proton therapy – SEER-Medicare data for men diagnosed with localized prostate cancer after 2002 – CPT codes used to identify men receiving external beam radiation as initial primary therapy – Comorbidity scores calculated by NCI Combined Index – Evaluation of morbidities, posttreatment interventions, and salvage therapies as surrogate for disease control – Propensity Score Adjustment used to minimize biasSheets NC, et al. ASCO GU 2012. Abstract 3.
    • 15. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Comparative Effectiveness of CRT, IMRT, PT For Localized Prostate Cancer: Results  IMRT (n = 6666) vs CRT  IMRT (n = 684) vs PT (n = 684) (n = 6310) – IMRT: lower incidence of bowel – Median follow-up: 4.5 yrs morbidity (P < .001) – IMRT associated with lower – All other morbidity outcomes incidence of bowel morbidity similar between cohorts (P < .001) and hip fracture – No difference in need for (P = .006) subsequent cancer control – IMRT associated with higher after radiation therapy incidence of erectile dysfunction (P = .006) – IMRT: reduced need for subsequent cancer therapy after radiation (P < .001)Sheets NC, et al. ASCO GU 2012. Abstract 3.
    • 16. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology ALSYMPCA: Phase III Trial of Radium-223 in Symptomatic Prostate Cancer Randomized 2:1 Up to 6 treatments at 4-wk intervals Radium-223 Patients with (50 kBq/kg) symptomatic CRPC and + ≥ 2 bone metastases Best standard of care with no known visceral metastases, either post- Stratified by total ALP, previous docetaxel, docetaxel or unfit for and bisphosphonate use docetaxel Placebo (saline) + (N = 921) Best standard of care  Primary endpoint: OS  Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, ALP normalization, time to PSA progression, safety, QoLParker C, et al. ASCO GU 2012. Abstract 8.
    • 17. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology ALSYMPCA: OS With Radium-223  OS improved significantly with radium-223 vs placebo  Median OS 100 HR: 0.695 (95% CI: 80 0.552-0.875; P = .00185) – Radium-223: 14.0 mos Patients (%) 60 Radium-223: n = 541 – Placebo: 11.2 mos 40 Median OS: 14.0 mos 20 Placebo: n = 268 Median OS: 11.2 mos 0 0 6 12 18 24 30 36 36 36 42 Mo Radium-233 541 450 330 213 120 72 30 15 3 0 Placebo 268 218 147 89 49 28 15 7 3 0Parker C, et al. ASCO GU 2012. Abstract 8.
    • 18. 2012 Genitourinary Cancers Symposium: Highlights clinicaloptions.com/oncology ALSYMPCA: Time to First SRE With Radium-223  Median time to first SRE significantly prolonged with radium-223 – Radium-223: 13.5 mos – Placebo: 8.4 mos Patients, n (%) 100 First SRE Radium-223 Placebo HR: 0.610 (95% CI: 0.461-0.807; P Value* Component Patients Without SRE 80 P = .00046) (n = 541) (n = 268) External 122 (23) 72 (27) .0038 Radium-223: n = 541 beam 60 Median OS: 13.5 mos radiotherapy (%) 40 Spinal cord 17 (3) 16 (6) .016 Placebo: n = 268 compression 20 Median OS: 8.4 mos Pathologic 20 (4) 18 (7) .013 bone fracture 0 0 3 6 9 12 15 18 21 Surgical 9 (2) 5 (2) .69 intervention Mo *Not adjusted for multiplicityRadium-233 541 379 214 111 51 22 6 0Placebo 268 159 74 30 15 7 2 0 Sartor O, et al. ASCO GU 2012. Abstract 9.
    • 19. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology ALSYMPCA: Toxicity All Grades Grades 3 or 4 Patients With AEs, n (%) Radium-223 Placebo Radium-223 Placebo (n = 509) (n = 253) (n = 509) (n = 253) Hematologic  Anemia 136 (27) 69 (27) 54 (11) 29 (12)  Neutropenia 20 (4) 2 (1) 9 (2) 2 (1)  Thrombocytopenia 42 (8) 14 (6) 22 (4) 4 (2) Nonhematologic  Bone pain 217 (43) 147 (58) 89 (18) 59 (23)  Diarrhea 112 (22) 34 (13) 6 (1) 3 (1)  Nausea 174 (34) 80 (32) 8 (2) 4 (2)  Vomiting 88 (17) 32 (13) 10 (2) 6 (2)  Constipation 89 (18) 46 (18) 6 (1) 2 (1)Parker C, et al. ASCO GU 2012. Abstract 8.
    • 20. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Phase I/II Open-Label Study: Ipilimumab in Metastatic CRPC  Men with progressive mCRPC after discontinuation of antiandrogen therapy, ECOG PS 0/1, and ≤ 1 previous docetaxel therapy (N = 71)  Dosing schedule – IPI: every 3 wks up to 4 doses, then every 12 wks if benefit observed – XRT: 8 Gy/target lesion up to 3 lesions/patient within 24-48 hrs of initial ipilimumab – Phase I dose escalation: ipilimumab 3, 5, or 10 mg/kg; then 3 or 10 mg/kg + XRT (at least 6 patients/cohort) – Phase II: expansion of ipilimumab 10 mg/kg and 10 mg/kg + XRT cohorts  Endpoints: safety, responseSlovin SF, et al. ASCO GU 2012. Abstract 25.
    • 21. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Phase I/II Open-Label Study of Ipilimumab in Metastatic CRPC: Toxicity  No DLTs observed  Most treatment-related AEs were grade 1/2 immune-related events, manageable by corticosteroids, HRT, and supportive control  Grade 3/4 immune-related AEs in the 10 mg/kg ipilimumab–XRT cohort – Grade 3 colitis: 16% – Grade 3 diarrhea: 8% – Grade 3/4 hepatitis: 4%/6%  1 treatment-related death in 5-mg/kg cohort attributed to aspergillosis after prolonged immunosuppression for grade 3 colitis  No exacerbation of AEs with addition of XRT to ipilimumab 10 mg/kgSlovin SF, et al. ASCO GU 2012. Abstract 25.
    • 22. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Phase I/II Open-label Study of Ipilimumab in Metastatic CRPC: Response All Treated Patients  Clinical antitumor activity 400 Day 85 400 At Any Time Percent Change Percent Change 300 300 with ipilimumab 10 mg/kg From Baseline From Baseline 200 200 alone or with XRT 100 100 0 0 – PSA decline, typically by -100 -100 Day 85 0 10 20 30 40 50 60 Patients (N = 85) 70 0 10 20 30 40 50 60 Patients (N = 85) 70 Ipilimumab 10 mg/kg Alone Cohort – Soft tissue tumor control 400 Day 85 400 At Any Time Percent Change Percent Change From Baseline From Baseline  Response (ipilimumab 10 mg/kg ± XRT) 0 0 – CR: 1 -100 -100 0 3 5 7 9 11 13 15 0 3 5 7 9 11 13 15 – Time to response: 2.5 mos Patients (N = 15) Patients (N = 15) Ipilimumab 10 mg/kg + XRT Cohort – SD lasting 2.8-6.1 mos: 6 200 Day 85 200 At Any Time Percent Change Percent Change From Baseline From Baseline 100 100 0 0 -100 -100 0 10 20 30 0 10 20 30Slovin SF, et al. ASCO GU 2012. Abstract 25. Patients (N = 30) Patients (N = 30)
    • 23. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Cixutumumab or Ramucirumab + MP in mCRPC After Progression on Docetaxel Stratified by ECOG PS, pain, response on previous Arm A docetaxel Cixutumumab 6 mg/kg qw Mitoxantrone 12 mg/m2 q3w max: 12 cycles Patients with mCRPC, Prednisone 5 mg PO BID ECOG PS 0-2, and (n = 66) disease progression during or within 120 days after docetaxel Arm B (N = 132) Ramucirumab 6 mg/kg qw Mitoxantrone 12 mg/m2 q3w max: 12 cycles Prednisone 5 mg PO BID (n = 66)  Primary endpoint: composite PFS  Secondary endpoints: safety, PFS over time, OS, ORR, PKHussain M, et al. ASCO GU 2012. Abstract 97.
    • 24. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Cixutumumab or Ramucirumab + MP in mCRPC With PD Post-Docetaxel: Safety  Cixutumumab and ramucirumab regimens well tolerated in most patients with docetaxel-resistant CRPC  Most frequently reported AE: fatigue  Incidence of most grade 3 or 4 nonhematologic AEs < 10% Treatment-Emergent Arm A (Cix) (n = 66) Arm B (Ram) (n = 66) Hematologic AEs, % Any Grade Grade Any Grade Grade Grade 3 4 Grade 3 4 Neutropenia 40.9 16.7 15.2 37.9 24.2 9.1 Anemia 36.4 4.5 0 36.4 10.6 0 Leukopenia 31.8 16.7 6.1 25.8 15.2 1.5 Thrombocytopenia 19.7 4.5 1.5 34.8 7.6 0Hussain M, et al. ASCO GU 2012. Abstract 97.
    • 25. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Cixutumumab or Ramucirumab + MP in mCRPC With PD Post-Docetaxel: Safety  Incidence of cardiac dysfunction greater in ramucirumab arm  No grade 4 or 5 cardiac failures reported Arm A (CIX) Arm B (RAM) Cardiac Function: LVEF Results (n = 66) (n = 66) n % n % LVEF reduced by > 10% from pretreatment level 8 12.1 22 33.3 Baseline LVEF ≥ 70% + LVEF decrease by > 10%, 3 4.5 4 6.1 to level ≥ 55% LVEF decreased to ≤ 35% 1 1.5 5 7.6 AE of LV dysfunction, reduced LVEF or CHF 8 12.1 15 22.7 AE of LV dysfunction, reduced LVEF or CHF: grade 3 0 0 5 7.6 Discontinuation of any study therapy due to reduced 6 9.1 11 16.7 LVEF or CHFHussain M, et al. ASCO GU 2012. Abstract 97.
    • 26. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Cixutumumab or Ramucirumab + MP in mCRPC With PD Post-Docetaxel: Efficacy  Moderate disease control in mCRPC with cixutumumab or ramucirumab in combination with mitoxantrone and prednisone – Cixutumumab – Median cPFS: 4.1 mos (95% CI: 3.0-5.6) – Preliminary median OS: 10.8 mos – 1-yr survival: 41.6% – Ramucirumab – Median cPFS: 6.7 mos (95% CI: 4.5-8.3) – Preliminary median OS: 13.0 mos – 1-yr survival: 54.2%Hussain M, et al. ASCO GU 2012. Abstract 97.
    • 27. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology First-Line OGX-427 + Prednisone vs Prednisone in mCRPC  OGX-427: synthetic oligonucleotide inhibitor of Hsp27 gene expression OGX-427 600 mg IV x 3. loading doses Patients with within 10 days, then 1000 mg IV weekly +progressive mCRPC Prednisone 5 mg PO BIDwho received no prior chemotherapy for metastatic disease (N = 33) Prednisone 5 mg PO BID* *Crossover allowed upon disease progression  Primary endpoint: PD at 12 wks  Secondary endpoints: PSA decline, measurable disease response, PFS, TTP, CTC count, serum/plasma HSP27Chi KN, et al. ASCO GU 2012. Abstract 121.
    • 28. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology OGX-427/Prednisone in mCRPC: Results Outcome, n (%) OGX-427/Prednisone Prednisone Disease progression at 12 wks (n = 14) (n = 12)  No disease progression 10 (71; 95% CI: 42% to 92%) 4 (33; 95% CI: 10% to 86%)  Disease progression 4 (29) 8 (67) Best PSA decline from baseline (n = 17) (n = 16)  ≥ 80% 2 (12) 1 (7)  ≥ 60% 7 (41) 3 (20)  ≥ 30% 10 (69) 6 (33)  Any 13 (78) 8 (53) Measurable disease response (n = 8) (n = 9)  PR 3 (38) 0  SD 1 (13) 4 (44)  PD 0 2 (22) Best CTC change from baseline, per 7.5 mL (n = 14) (n = 12)  ≥ 5 to < 5 7 (50) 4 (31)  < 5 to < 5 1 (7) 1 (8)  ≥ 5 to ≥ 5 6 (43) 8 (61)Chi KN, et al. ASCO GU 2012. Abstract 121.
    • 29. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology OGX-427/Prednisone for mCRPC: Toxicity Incidence of All Laboratory OGX-427 + Prednisone Prednisone Treatment-Emergent Events (n = 17) (n = 15) Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 All, % 76% 24% 80% 20% Lymphopenia, n 10 3 12 2 Anemia, n 12 0 10 0 Hyperglycemia, n 12 1 7 1 Elevated creatinine, n 3 1* 6 0 Elevated AST/ALT, n 9 0 0 0 Thrombocytopenia, n 6 1 2 0 Hyponatremia, n 3 1 2 0 Hypokalemia, n 4 0 2 0 *1 case of grade 4 hemolytic uremic syndrome reported at Wk 7.Chi KN, et al. ASCO GU 2012. Abstract 121.
    • 30. Renal Cell Carcinoma
    • 31. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Phase II Study: Personalized DC-Based Therapy (AGS-003) + Sunitinib for mRCC  AGS-003: fully personalized immunotherapy – RNA-loaded DCs – Stimulates tumor-targeted cytotoxic T lymphocyte proliferation Newly diagnosedadults with advanced Pretreatment Treatment Booster stage RCC, ECOGPS 0-1, who had no Diagnosis Sunitinib AGS-003 AGS-003 previous systemic therapy Screening 1 cycle* 5 doses, quarterly Nephrectomy 3 wks apart until PD (N = 21) Leukapheresis *6-wk cycles: 4 wks on, Sunitinib continuing until PD 2 wks off  Primary endpoint: objective tumor response (RECIST)  Secondary endpoints: CBR, OS, PFS, immune response, and safetyFiglin RA, et al. ASCO GU 2012. Abstract 348.
    • 32. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AGS-003 + Sunitinib in mRCC: Efficacy  PR: 8 (38%); 3 after prolonged booster phase  Median PFS: 11.2 mos  CBR (PR + SD): 13 (62%)  Median OS: 29.3 mos (Kaplan-Meier)  Immunologic response: 11/15 (73%) Induction of CD28+CD45RA- T Cells Correlates* With OS OS by Subject (N = 21) 300 621 1841 % Change in 250 Effector/Memory 200 *Patients ongoing without progression T Cells Between 150 Baseline and Fifth100 = Alive in active OS follow-up AGS-003 Dose 50 0 -50 -100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Subject Registration (Mos) * 40 = Alive in active follow up * 35 * OS From 30 25 20 16 10 5 0 5 10 15 20 25 30 35 40 0 OS From Registration (Mos) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Subject 3 subjects remain on study protocol without PD; 8 subjects still alive; *Highly significant by nonparametric bivariate analysis (P = .0061) 9 subjects (43%) experienced OS > 30 mosFiglin RA, et al. ASCO GU 2012. Abstract 348.
    • 33. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AGS-003 + Sunitinib in mRCC: Safety  21 subjects have received > 150 doses of AGS-003  No AGS-003–related grade 3/4 AEs reported; grade 3/4 hematologic AEs attributable to sunitinib included leukopenia (8%), anemia (4%), and thrombocytopenia (4%)  Grade 1 AEs attributable to AGS-003 included injection-site erythema and injection-site induration, occurring in 33.3% and 23.8% of subjects, respectively  All other observed AEs consistent with previous findings for sunitinib in advanced RCC  No emergent autoimmune disease observedFiglin RA, et al. ASCO GU 2012. Abstract 348.
    • 34. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Phase II MET111644 Study: Foretinib in Patients With Papillary RCC  Multicenter, prospective phase II and biomarker, open-label, single-stage study Patients with confirmed Intermittent Cohort sporadic or hereditary Foretinib 240 mg/day, Days 1-5 every 14 days papillary RCC, ECOG PS 0-2, and ≤ 1 previous systemic Stratified by MET mutation status therapy Daily Cohort (N = 74) Foretinib 80 mg/day  Primary endpoint: ORR by RECIST 1.0  Secondary endpoints: PFS, OS, safety, correlation of outcome with PK, PD, METChoueiri TK, et al. ASCO GU 2012. Abstract 355.
    • 35. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology MET111644: Foretinib Efficacy Outcome Intermittent Dosing Daily Dosing Total (n = 37) (n = 37) (N = 74) ORR n (%) 5 (13.5) 5 (13.5) 10 (13.5) DOR: 18.5 mos Disease stabilization rate (ORR + SD): 88% Median PFS, mos 11.6 9.1 9.6 Median OS Not reached Not reached Not reached 1-yr OS, % 64 76 70  Evidence of tumor shrinkage in 50/68 evaluable patients  Significant modulation of VEGF, HGF, sMET, sVEGFR2 suggestive of MET pathway inhibition in both arms; not strongly correlated with outcomesChoueiri TK, et al. ASCO GU 2012. Abstract 355.
    • 36. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology MET111644: Foretinib Toxicity Treatment-Related Toxicity All Grades, Grade 3/4, (N = 74) n (%) n (%) Hypertension 60 (81.0) 38 (51.0) Fatigue 45 (73.0) 5 (7.0) Diarrhea 41 (55.0) 7 (9.5) Laboratory toxicities (≥ 10%)  Hypophosphatemia 17 (23.0) 0  Proteinuria 16 (22.0) 4 (5.0)  Increased lipase 14 (19.0) 7 (9.5)  ALT elevation 13 (17.0) 1  AST elevation 13 (17.0) 2 (3.0)  Hypothyroidism 12 (16.0) 0  Thrombocytopenia 8 (11.0) 1 (1.4)Choueiri TK, et al. ASCO GU 2012. Abstract 355.
    • 37. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AXIS: Axitinib vs Sorafenib in Refractory mRCC, Secondary Analyses[1] Stratified by ECOG PS and type of previous treatment Patients with clear-cell Axitinib 5 mg BID* mRCC progressing after (n = 361) 1 previous systemic first- line regimen including *Starting dose 5 mg BID with option for sunitinib, bevacizumab + dose titration to 7 mg BID, then to a maximum IFN-α, temsirolimus, or of 10 mg BID. cytokines Sorafenib 400 mg BID (N = 723) (n = 362)  Primary endpoint: PFS significantly prolonged with axitinib vs sorafenib[2] – Median PFS with axitinib vs sorafenib: 6.7 mos (95% CI: 6.3-8.6) vs 4.7 mos (95% CI: 4.6-5.6); HR: 0.665 (95% CI: 0.544-0.812; P < .0001)  Secondary analyses: effect of dose titration and previous first-line treatment duration and response on axitinib efficacy1. Rini BI, et al. ASCO GU 2012. Abstract 354^. 2. Rini BI, et al. Lancet. 2011;378:1931-1939.
    • 38. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AXIS Results: Patient Disposition Starting dose 5 mg BID N = 359 Highest titration to 7 mg BID (100%) n = 60 (17%) Mean duration (7 mg/BID): Dose Dose 92 days reduction No dose Dose after reduction change escalation increase < 5 mg Highest titration to 10 mg BID 5 mg BID > 5 mg BID n = 71 (20%) BID n = 71 (20%) n = 139 n = 132 n = 88 (39%) (37%) Mean duration (10 mg/BID): (25%) 127 daysRini BI, et al. ASCO GU 2012. Abstract 354^.
    • 39. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AXIS Dose Titration Analysis: Results  PFS similar with axitinib ≤ 5 mg BID and > 5 mg BID; Progression-Free Survival both superior to PFS with 1.00 sorafenib Survival Distribution Function Axitinib ≤ 5 mg BID  Incidence of AEs similar Axitinib > 5 mg BID with axitinib ≤ 5 mg BID 0.75 Sorafenib and > 5 mg BID – Slightly increased in dose- 0.50 titrated patients: nausea, asthenia, decreased appetite 0.25 – Slightly decreased in dose-titrated patients: 0 hypothyroidism, proteinuria, 0 2.5 5.0 7.5 10.0 12.0 15.0 17.5 20.0 hypertension MosRini BI, et al. ASCO GU 2012. Abstract 354^.
    • 40. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology AXIS: PFS by Previous Response to Sunitinib Axitinib Sorafenib  PFS similar with axitinib mPFS, mPFS, ≤ 5 mg BID and > 5 mg BID; n Mos 95% CI n Mos 95% CI Nonresponders 145 4.8 4.2-6.7 Nonresponders 143 3.0 2.8-4.6 both superior to PFS with Responders 47 4.6 2.8-6.3 Responders 52 4.7 2.9-6.6 sorafenib 1.00 1.00  Trend toward increased PFS 0.80 0.80 for patients receiving sunitinib Probability PFS Probability PFS for > 9 mos 0.60 0.60  Previous objective response 0.40 0.40 on sunitinib not correlated to PFS with axitinib 0.20 0.20 0 0 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 Mos Mos PFS by Duration of Previous Sunitinib, Mos (95% CI; n) Agent < 3 vs ≥ 3 mos < 6 vs ≥ 6 mos < 9 vs ≥ 9 mos Axitinib 4.5 4.8 4.6 4.8 4.5 6.3 (2.7-NR; 22) (4.5-6.5; 170) (2.8-8.3; 48) (3.6-6.5; (2.8-6.4; 90) (4.6-6.7; 102) Sorafenib 2.8 3.7 2.8 4.6 144) 2.9 4.6 (1.4-15.7; (2.8-4.7; 173) (1.6-3.7; 62) (2.9-4.9; (2.8-4.6; 87) (2.9-4.9; 107)Rini BI, et al. ASCO GU 2012. Abstract 354^. 21) 132)
    • 41. Testicular Cancer
    • 42. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Long-term Outcomes After Radiotherapy for Stage II Testicular Seminoma  Patients with stage II testicular seminoma given RT at Mayo Clinic between 1974-2007: N = 49 – Median age at diagnosis: 35 yrs (range: 22-71) – CT staging (AJCC 7th edition) available for 46 patients – IIA: 23 (47%); IIB: 7 (14%); IIC: 15 (31%); II NOS: 4 (8%) – 3 patients: RT for PA recurrence after stage I seminoma – 4 patients: RT and chemotherapy due to bulky disease  Abdominal/pelvic RT field  Median infradiaphragmatic RT dose: 30.4 Gy (range: 13.3 - 44.7) – PA + bilateral pelvis: 25 (51%)  Prophylactic MSCV RT: 24 (49%) – PA + ipsilateral pelvis: 21 (43%) – PA only: 3 (6%)  Median MSCV RT dose: 20 Gy (range: 12-30)Hallemeier CL, et al. ASCO GU 2012. Abstract 327.
    • 43. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Long-Term Outcomes After RT for Stage II Testicular Seminoma Outcome Patients Relapse-Free Survival Estimates (KM) 1.00 Relapse-Free Survival IIA 10/20-yr OS, % 94/81 0.8 (n = 23) 10/20-yr CSS, % 96/96 0.6 IIC (n = 15) Recurrence, n (%) 9 (18)* 0.4 IIB (n = 7)  MSCV regions, n 6 0.2 P = .37  PA nodes, n 1 0 0 5 10 15 20  Lung parenchyma, n 1 Yr  Peritoneal cavity, n 1 Relapse Risk Estimates (KM) Major cardiac events, n (%) 10 (20) 1.00 P = .04 Second malignancy, n (%) 5 (10) 0.8 Relapse 0.6 IIB, no MSCV RT (n = 7) *7 of 9 recurrences successfully salvaged with chemotherapy. 0.4  Risk of MSCV failure significantly associated with IIA, no MSCV RT (n = 13) 0.2 intradiaphragmatic RT alone, particularly in stage IIB IIA/B MSCV RT (n = 11) 0  MCE, SM occurred at median 18 yrs (range 7-30), 0 5 10 27 yrs (range 20-34) post-RT, respectively YrHallemeier CL, et al. ASCO GU 2012. Abstract 327.
    • 44. Urothelial Cancer
    • 45. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology BCL2L1 and TACC3 SNPs Associated With BCG Response in Nonmuscle-Invasive BC  Genotyping study: can SNPs predict response to BCG intravesical therapy in nonmuscle-invasive bladder cancer?  Patients with NMIBC who received 6 doses of BCG (± maintenance) as first-line therapy postresection (N = 158) – Genotyping with 80 SNPs selected from published studies – Urothelial cancer risk – DNA damage repair – Inflammation – Immune reactions – Anonymous linking of genotype and response data – Determination of association between each SNP and BCG response  Results tested in an independent patient cohort (N = 168)Alanee S, et al. ASCO GU 2012. Abstract 260.
    • 46. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology BCL2L1 and TACC3 SNPs Associated With BCG Response in NMIBC: Results[1]  2 SNPs significantly associated with BCG response by multivariate analysis (n = 158) – rs798766 inTACC3 (OR: 3.4; P = .01) – rs1994251 in BCL2L1 (OR: 3.2; P = .02) – Validation confounded by institutional variation in treatment outcome  12 SNPs previously reported as predictive of BCG response not validated  Analysis of a cohort controlled for confounders (N = 276) revealed 1 SNP predictive of refractory disease, not previously associated with BCG – rs11615 in ERCC – Nucleotide excision repair pathway – Associated with cisplatin cytotoxicity in gastric, ovarian, colorectal cancers[2,3] – 33% of patients with CC genotype of rs11615 were BCG refractory vs 11% with TT genotype (OR: 1.8; 95% CI: 1.14-3; P =.01)1. Alanee S, et al. ASCO GU 2012. Abstract 260. 2. Smith S, et al. J Clin Oncol. 2007;25:5172-5179.3. Gangawar R, et al. Med Oncol. 2010;27:159-166.
    • 47. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Pooled Analysis of Long-term Outcomes in MIBC After Bladder-Preserving CMT  Pooled analysis (N = 468) of long-term outcomes from RTOG studies of combined-modality therapy for muscle- invasive bladder cancer – Phase II: RTOG 8802, 9506, 9706, 9906, and 0233 – Phase III: RTOG 8903  OS estimated by Kaplan-Meier method  DSS, local failure, and distant metastases estimated by cumulative incidence method  Clinical variables associated with DSS identified by Fine and Gray’s proportional hazard regression modelMak RH, et al. ASCO GU 2012. Abstract 264.
    • 48. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Pooled Analysis of Long-term Outcomes in MIBC After Bladder-Preserving CMT  Long-term outcomes with bladder-preserving CMT comparable to outcomes reported for previous single-institution series  Decreased OS, DSS associated  Improved DSS associated with with higher clinical stage complete response to CMT 100 Clinical OS DSS 78.8% Stage, % Disease-specific (P = .002) (P = .05) 75 Survival (%) 56.0% 5 Yr 10 Yr 5 Yr 10 Yr 50 T2 62 41 74 69 Failed Total 25 Complete responders 78 321 T3/T4 49 30 66 60 Nonresponders 59 125 P < .0001 0 0 1 2 3 4 5 Yrs After Randomization Patients at Risk, n Complete responders 321 299 258 225 190 164 Nonresponders 125 104 77 54 49 40Mak RH, et al. ASCO GU 2012. Abstract 264.
    • 49. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Neoadjuvant DD-MVAC + Bevacizumab in High-Risk Urothelial Cancer: Phase II Trial  Patients with bladder cancer or upper tract tumor: N = 60  Dosing regimen – Bevacizumab 10 mg/kg, then – Methotrexate 30 mg/m2 + vinblastine 3 mg/m2 + doxorubicin 30 mg/m2 + cisplatin 70 mg/m2 (DD-MVAC) – Agents given over Days 1-2, every 2 wks with 3L mannitol infusion and IV pegfilgrastim – 4 cycles of therapy  Surgery minimum of 6 wks after last bevacizumab dose  Primary endpoint: pathologic down-staging to ≤ pT1N0  Secondary endpoints: OS, DSS, tolerabilitySiefker-Radtke AO, et al. ASCO GU 2012. Abstract 261.
    • 50. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Neoadjuvant DD-MVAC + Bevacizumab in High-Risk Urothelial Cancer: Results Survival at Median Follow-up of 26 Mos, OS DSS % 2 Yr 3 Yr 2 Yr 3 Yr All patients 78 63 82 64 Bladder/urethra (n = 44) 75 52 78 54 Upper tract (n = 16) 93 93 93 93  Significant improvement in OS, DSS DSS by pStage with down-staging to ≤ pT1N0M0 1.0 0.9  Down-staging to ≤ pT1N0: 53% Relapse-Free Survival 0.8 – Bladder/urethra: 45% 0.7 0.6 – Upper tract: 75% 0.5  Down-staging to ≤ pT0N0: 38% 0.4 3 Yr OS DSS Med 0.3 pStage T0-T2N0 97% 97% NR – Bladder/urethra: 39% 0.2 pStage T3b-T4aN0 66% 83% NR pStage T4b, N+ or M+ 24% 24% 17 mos – Upper tract: 38% 0.1 P = .00026 0 0 12 24 36 48 60 Survival Time (Yr)Siefker-Radtke AO, et al. ASCO GU 2012. Abstract 261.
    • 51. 2012 Genitourinary Cancers Symposium: Highlightsclinicaloptions.com/oncology Neoadjuvant DD-MVAC + Bevacizumab in High-Risk Urothelial Cancer: Tolerability  Chemotherapy – Patients completing 4 cycles of chemotherapy: 51 (85%) – Grade 3 or 4 neutropenia or neutropenic fever: 17% and 4%, respectively – Grade 3 mucositis: 3%  Surgery – Cystectomy: 43 –Nephrectomy/nephroureterectomy: – Median hospital stay: 9 days 16 – Hospital stay > 11 days: 23% – Median hospital stay: 4 days – Hospital stay > 11 days: 13%Siefker-Radtke AO, et al. ASCO GU 2012. Abstract 261.
    • 52. Go Online for More CCO Coverage of Genitourinary Cancers!clinicaloptions.com/oncology

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