Welcome to OncoFacts for May, 2010. In this month’s edition, we are going to report some of the data presented at the 2010 Genitourinary Cancers Symposium.

Androgen Receptor Targeted Strategies

Charles Ryan gave an excellent, clear, and comprehensive presentation on the role of androgen signaling in prostate cancer and the attempts to abrogate its effects. He pointed out that androgen signaling begins with the production of testosterone through the adrenal androgen synthesis pathway leading to circulation and transport of androgens into cells, conversion of testosterone to dihydrotestosterone (DHT), the most active ligand for the receptor, and finally binding to the androgen receptor (AR) that initiates a cascade of proliferation and survival events. Androgen receptor targeted strategies begin with attempts to block androgen synthesis with CYP17 inhibitors. Ketoconazole has been used for this purpose and is capable of blocking adrenal production of all steroids. A much more potent CYP17 inhibitor, abiraterone, is progressing through the clinical trial process and is now in phase III trials in castrate-resistant prostate cancer (CRPC). A phase II trial has recently been published in the Journal of Clinical Oncology. Abiraterone is 10 times more potent at blocking the CYP17 enzymes than is keotoconazole and produce prostate-specific antigen (PSA) responses in over 50% of patients with CRPC, whether they were previously treated with chemotherapy or not. It also has activity in patients previously exposed to ketoconazole. Some responses are very durable lasting more than 1 year and complete responses have been seen. Many remaining questions regarding abiraterone will be the subject of future investigations. These include:

1. What is the mechanism of resistance since androgen levels remain very low even in the face of disease progression on abiraterone?
2. Should abiraterone be continued beyond progression as is done with the gonadotropin-releasing hormone (GnRH) agonists?
3. What is the effect of abiraterone on intracrine androgen production?
4. Should abiraterone be utilized earlier in the course of prostate cancer to prevent metastasis or as initial androgen depravation therapy (ADT)?
5. Are there variants of prostate cancer that are more or less susceptible to abiraterone?
6. What is the disease that persists after treatment with a secondary androgen deprivation therapy, such as abiraterone, when the circulation and the microenvironment are both deprived of androgens?

Another method of blocking androgen signaling is by blocking androgen transport into the cell. A novel agent HE-3235 (apoptone) is thought to inhibit membrane steroid receptors blocking androgen transport into cells, but it may have many other mechanisms of action as well. It is still in phase I studies.

Blocking the conversion of testosterone to DHT can be accomplished with 5-alpha-reductase inhibitors, such as dutasteride, although much higher doses are required than for benign prostatic hyperplasia (BPH). Trials are underway combining dutasteride with ketoconazole. Another group of compounds known as sulfatase inhibitors block the conversion of dehydroepiandrosterone sulfate (DHEAS) to dehydroepiandrosterone (DHEA) that is then available for conversion to androstenediol. BN-83495 is a sulfatase inhibitor in phase I trials.

The final method of blocking androgen signaling is through inhibition of the AR itself. Androgen receptor amplification is extremely common in CRPC. Increases in AR gene copy number, as well as multiple genomic aberrations, are frequently noted in CRPC specimens. Novel androgen receptor inhibitors are in clinical trials. MDV3100 is in phase III, and ARN-509 is in phase I. MDV3100 has produced greater than 50% PSA responses in patients with CRPC whether previously exposed to chemotherapy or not. Phase III trials are moving forward rapidly.

Questions remain concerning the possible role of MDV3100 in the non-castrate setting and the potential for combination therapy with agents such as CYP17 inhibitors and novel AR inhibitors producing maximum combined androgen blockade.

Abstract # 5
PCA3 is a segment on non-coding messenger ribonucleic acid (mRNA) localized to chromosome 9q21-22. It is over-expressed in 95% of prostate cancers, and its expression is 60 - 100 times greater in prostate cancer tissue compared to BPH tissue. It is measured in the urine after a digital rectal exam (DRE) and is reported as a score that is the ratio of the mRNA of PCA3 to the mRNA of PSA. The PCA3 test is produced by Gen-Probe. Previous studies have demonstrated that the PCA3 score correlates with the likelihood of a positive prostate biopsy in men with elevated PSA levels who have had a negative prior biopsy.

The current abstract concerned a PCA3 validation study utilizing the study population from the dutasteride versus placebo prostate cancer prevention trial, REDUCE. Men ages 50-75 with PSA values of 2.5 - 10 and a negative prostate biopsy within the past 6 months were eligible. Urine specimens were obtained after DRE at years 2 and 4, frozen and stored. Prostate biopsy samples were obtained from 1140 men by year 4. Eighty-two percent were negative, 18% were positive, of which 30% had Gleason scores of 7 or greater. The urine PCA3 score was found to correlate with the likelihood of a positive prostate biopsy result. A score of 35 produced the best cutoff for sensitivity and specificity. The PCA3 score was more sensitive in predicting a positive biopsy result than was the PSA or free PSA. If the score was <5, there was only a 6% chance of the prostate biopsy result being positive. At a PCA3 score of 35, there was a 22% chance of a biopsy result being positive, and at a score of >100, the chance of a positive biopsy result was 57%. The authors concluded that the PCA3 score predicts for a positive biopsy result, that a score of 35 was the best cutoff for sensitivity and specificity, and that the score correlates with Gleason score in the positive biopsy results.

Abstract # 8
The IMPACT trial randomized 512 men with CRPC in a 2:1 fashion to sipuleucel-T or placebo. Sipuleucel-T is a cell based cancer therapeutic vaccine. Eligible patients underwent leukopheresis, and their cells, including antigen presenting cells, were then exposed to a recombinant fusion protein consisting of prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor (GM-CSF). The antigen presenting cells were then re-infused every 2 weeks for a total of 3 doses. The placebo group’s leukopheresed cells were frozen and later used to produce a similar vaccine, APC8015F, to be used in a crossover fashion if desired upon disease progression. Five hundred twelve patients were randomized with stratification for bisphosphonate use, Gleason score, number of bone metastases, PSA level, and serum lactate dehydrogenase (LDH). The primary endpoint was overall survival (OS) with time to objective disease progression was the secondary endpoint. Using the Halabi nomogram, the anticipated survival for the 2 groups was in the range of 21 months. After 349 deaths among the study population, the survival benefit from sipuleucel-T at 25.8 months was 4.1 months greater than for the placebo group at 21.7 months with a hazard ratio (HR) of 0.759.

A forest plot demonstrated that the survival benefit was seen across all disease subsets. Among patients who received docetaxel following the trial, survival was greater for the patients treated with sipuleucel-T with a HR of 0.649. There was no difference in the time to objective disease progression. The authors stated that response rate and time to tumor progression (TTP) may not be appropriate endpoints for trials with immune therapy since the responses were often delayed and prolonged. Results from this randomized phase III trial were felt to be similar to the smaller phase II trials, 9901 and 9902A. They felt that this study represented a new treatment paradigm in prostate cancer and that sipuleucel-T was the first active immunotherapy to demonstrate improvement in OS in metastatic prostate cancer.

Abstract # 9
Cabazitaxel is a semi-synthetic taxane that acts as a microtubule stabilizer. In phase I studies, neutropenia was the dose limiting toxicity and activity was seen in heavily pre-treated patients with CRPC. Docetaxel-prednisone is the standard chemotherapy regimen for CRPC. In the TAX 327 trial, it produced an OS of 19.2 months vs 16.3 months for mitoxantrone-prednisone with a HR of 0.76. However, for patients whose disease has progressed post-docetaxel, there has been no standard of care.

The TROPIC trial was performed in 26 countries at 146 sites. Seven hundred fifty-five patients whose CRPC had progressed after receiving a median of 7 cycles - 7.5 cycles of docetaxel with an average exposure of 530 mg/m² - 576 mg/m² were randomized 1:1 to cabazitaxel plus prednisone versus mitoxantrone plus prednisone. Over 50% of patients had measureable disease, and 25% had visceral disease. The majority of patients had received their last dose of docetaxel less than 3 months prior to randomization. Twenty-one percent of patients had had 2 prior chemotherapy regimens, and 8% had had 3 prior regimens. Median overall survival was the primary endpoint and was in favor of cabazitaxel at 15.1 months versus 12.7 months for mitoxantrone (HR = 0.70 and P<0.0001). Progression-free survival for cabazitaxel-prednisone (CP) was 2.8 months and for mitoxantrone-prednisone (MP) progression-free survival (PFS) was 1.4 months. Time to tumor progression was 8.8 months for CP and 5.4 months for MP. Objective tumor overall response rate (ORR) was 14.4% for CP vs 4.4% for MP, and PSA response rate was 39.2% vs 17.8%. Neutropenia, fatigue, diarrhea, and asthenia were the most common adverse events in the CP group. Death was due to disease progression in 74% of the patients who received MP and 61% of the patients who received CP. There were 7 adverse event related deaths in the MP group and 18 adverse event related deaths in the CP group, primarily related to neutropenia. The authors concluded that cabazitaxel-prednisone produced a statistically and clinically significant improvement in OS, PFS, ORR, and TTP.

Abstract # 311
Two prospective randomized controlled trials have demonstrated that cytoreductive nephrectomy (CN) improved OS from a median of 7.8 months to 13.6 months compared to interferon alone with a HR of 0.69. Whether CN would produce a similar benefit in the era of vascular endothelial growth factor (VEGF) targeted therapy remains undefined.

Dr Choueiri presented the results of a retrospective review performed by the Renal Cell Carcinoma Consortium consisting of Dana-Farber Cancer Institute, Cleveland Clinic, Beth Israel Med Center, and 4 Canadian cancer centers. Their database consisted of 645 patients with renal cell carcinoma (RCC) who had undergone nephrectomy from these 7 centers. Three hundred thirty-one patients were excluded because they had undergone nephrectomy for early-stage disease before they developed metastases. Three hundred fourteen patients with RCC, mostly with clear cell carcinoma, were included in the study of patients with RCC treated with VEGF targeted therapy. Two hundred one patients underwent CN and 113 did not. Overall, the patients who underwent CN tended to be younger, have better performance status, have a longer time from diagnosis to treatment, have worse renal function, be more likely to receive sorafenib, and have more sites of metastatic disease. Median OS was significantly better for the patients with RCC who underwent CN at 19.8 months versus 9.4 months for those who did not. The HR was 0.44 with a P-value of <0.001. Independent predictors for short OS in the era of VEGF targeted therapy included:

• Karnofsky performance status <80%
• Time from diagnosis to treatment <1 year
• Anemia
• Hypercalcemia
• Neutrophilia
• Neutrophilia

Patients with none of these features fell into the favorable-risk category. Those with 1 or 2 features fell into the intermediate-risk category and those with 3 to 6 features fell into the poor-risk category. Twenty-two of the 23 patients in the favorable-risk category underwent CN. Among the patients with intermediate-risk RCC, the OS benefit for CN was significant with a HR of 0.46 (P = .004). Among the patients with poor-risk RCC, the OS benefit for CN was borderline significant (P = .056) with a HR of 0.67.

The impact of CN by Karnofsky performance status (KPS) was important. If the KPS was 80% or higher, the median OS was 24 months with CN and 14.5 months without CN (P = .003). But if the KPS was <80%, the median OS was 10.1 months with CN and 6.0 months without CN (P = .077). Dr Choueiri and his co-authors acknowledged that this was a retrospective and not a prospective study and that it lacked central pathology review and external validation. But it was a large multicenter study including patients both on and off clinical trials and was conducted in the era of VEGF targeted therapy.

Abstract # 312
Hypertension is considered an on-target effect of VEGF targeted therapy. Sunitinib in particular has been associated with approximately a 30% incidence of any grade hypertension. VEGF-targeted therapy induced hypertension has been associated with improved clinical outcomes in multiple tumor types. This was a retrospective review of patients with RCC treated with sunitinib with the objective of evaluating the correlation between the development of hypertension in sunitinib treated patients with metastatic renal cell carcinoma (mRCC) and measures of anti-tumor efficacy, and also the development of hypertension-associated complications. Five hundred forty-four patients from 3 clinical trials were available for efficacy analysis, and 4917 patients from 3 clinical trials and the expanded access program were available for safety analysis. Hypertension was defined as a systolic BP of at least 140 mmHg and a diastolic BP of at least 90 mmHg at any time after initiation of sunitinib therapy for mRCC. Uncontrolled hypertension was an exclusion factor for 2 of the 4 trials included in the analysis. Of the 544 patients evaluated for efficacy, 82% developed hypertension according to systolic criteria, and 67% developed hypertension according to the diastolic criteria. Relative sunitinib dose intensity did not correlate with maximum systolic blood pressure. The median time to development of hypertension was the first or second cycle of therapy.

The median OS for patients who developed systolic hypertension was 30.9 months versus 7.2 months for those who did not develop hypertension with a P-value of <0.0001. Similar results were seen for diastolic hypertension with median OS of 32.2 months versus 14.9 months for those who did not develop diastolic hypertension. This impressive statistically significant advantage for the development of either systolic or diastolic hypertension was seen for objective response rate, PFS, and for OS. Treatment of the sunitinib-induced hypertension did not abrogate the beneficial effect of the development of hypertension in these patients with mRCC. When examined along with other prognostic factors through multivariate analysis, the development of hypertension remained a strongly significant independent factor for both PFS and OS. The incidence of grade 3 or higher renal adverse events was low in both groups of patients but was statistically higher in those developing hypertension. There was no difference in the development of any grade brain, eye, or heart related adverse events between those patients developing hypertension or not.

Abstract # 319
This was another retrospective review of patients with RCC from the 7-center RCC Consortium database. Patients included in this study had to have mRCC, previous sunitinib treatment with disease progression, at least 1 other anti-tumor therapy after sunitinib, and had to have received a second course of therapy with sunitinib. Investigator assessed response by RECIST criteria, and PFS needed to be recorded. Twenty-three such patients were identified. Baseline characteristics were fairly typical of advanced patients with RCC. Metastatic sites in order of frequency included lung, lymph nodes, bone, liver, adrenal, pancreas and brain. Fifty-seven percent of the patients had more than 2 metastatic sites of disease. Ninety-one percent had had a prior nephrectomy. The median exposure to sunitinib in the first course was 14 months and the best response was a partial respons (PR) for 67% of the patients. Progression-free survival from the first sunitinib course was 13.7 months and 87% of the patients by Memorial Sloan-Kettering Cancer Center Risk Group were of favorable-risk or intermediate-risk.

The interval between completion of the first course of sunitinib and the second course was 6.7 months with a range of 1.3 months - 22 months. Intervening treatments included VEGF inhibitors, m-TOR inhibitors, other treatments, radiation, and surgery. Sunitinib rechallenge resulted in a median duration of treatment of 6.8 months with 22% PR and 74% stable disease. Median PFS was 7.2 months. In 6 patients, their PFS with rechallenge was longer than the PFS with their first course of sunitinib. Patients with a >6 months interval between their first and second courses of sunitinib had a longer PFS than the patients whose interval was <6 months. The number of intervening treatments did not affect the degree of benefit from sunitinib rechallenge. Patients who achieved a PR with their initial sunitinib treatment were somewhat more likely to have a better PFS from rechallenge. The only sunitinib toxicities that appeared worse with rechallenge were fatigue and neutropenia, but that is not surprising for patients receiving their third, fourth, or greater line of treatment. The authors concluded that disease progression on sunitinib is not associated with absolute resistance to therapy.

Abstract # 318
In considering the topic presented in the title of this abstract Dr Abel asked the following questions.

What are the potential advantages of pre-surgical systemic therapy?

• Earlier initiation of systemic therapy
• Select patients who benefit most from nephrectomy
• Large complex tumors may decrease in size and make surgery easier
• Response in metastatic sites may improve peri-operative morbidity

What are the potential disadvantages of pre-surgical systemic therapy?

• Primary tumor may progress and make surgery more difficult
• Worse response rates in metastatic sites with primary tumor in situ
• Delays benefit from cytoreductive nephrectomy
• Toxicity of systemic therapy could make patient a worse surgical risk

Small case series have reported incidences of dramatic primary tumor responses with targeted systemic therapies. The investigators reviewed their patients with RCC treated with systemic therapy with the primary tumor in place to determine what response took place, when it took place, and what implications it had for surgery. They found 143 patients with a median tumor size of 8.65 cm. Just over 50% of patients had 2 or more metastatic sites. Initiation of systemic therapy was performed for the following reasons:

Forty percent received sunitinib, 36% received bevacizumab, 12% sorafenib and 7% temsirolimus. Median overall tumor shrinkage was 7.7%. However, all of the therapies produced minimal positive responses with only 5.6% PR by RECIST criteria of >30% tumor shrinkage. An additional 35% did have minor responses with tumor shrinkage of from 10% to 30%. Stable disease was seen in 51.7%. The patients who did best obtained their response early in the course of systemic therapy. The patients who achieved a >10% tumor shrinkage in the first 90 days received their maximum response of 24% tumor shrinkage at 195 days. Those who failed to experience at least 10% tumor shrinkage at 90 days had a maximum response of just over 10% at 188 days. The authors concluded that the median time to maximum response is 6 months and that the level of response seen at 90 days is predictive of overall response.

References
1. Ryan CJ, Jones J, Diamond M, et al. Role of mineralocorticoid elevation in the antiandrogen activity of abiraterone acetate. 2010 Genitourinary Cancers Symposium; Mach 5-7, 2010; San Francisco, CA. Abstract 109.

2. Groskopf J, Aubin SM, Reid J, et al. Validation of the PCA3 molecular urine test for predicting repeat prostate biopsy outcome in the placebo arm of the dutasteride REDUCE trial. 2010 Genitourinary Cancers Symposium; Mach 5-7, 2010; San Francisco, CA. Abstract 5.

3. Kantoff P, Higano CS, Berger ER, et al. Updated survival results of the IMPACT trial of sipuleucel-T for metastatic castration-resistant prostate cancer (CRPC). 2010 Genitourinary Cancers Symposium; Mach 5-7, 2010; San Francisco, CA. Abstract 8.

4. Sartor AO, Oudard S, Ozguroglu S, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational phase III trial (TROPIC). 2010 Genitourinary Cancers Symposium; Mach 5-7, 2010; San Francisco, CA. Abstract 9.

5. Choueiri TK, Xie W, Kollmannsberger CK, et al. The impact of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy. 2010 Genitourinary Cancers Symposium; Mach 5-7, 2010; San Francisco, CA. Abstract 311.

6. Rini BI, Cohen DP, Lu D, et al. Hypertension (HTN) as a biomarker of efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib. 2010 Genitourinary Cancers Symposium; Mach 5-7, 2010; San Francisco, CA. Abstract 312.

7. Reni BI, Hutson TE, Elson P, et al. Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma. 2010 Genitourinary Cancers Symposium; Mach 5-7, 2010; San Francisco, CA. Abstract 319.

8. Abel EJ, Tannir NM, Culp SH, et al. Does targeted therapy result in reliable and meaningful primary tumor downstaging in patients with metastatic renal cell carcinoma? 2010 Genitourinary Cancers Symposium; Mach 5-7, 2010; San Francisco, CA. Abstract 318.

To enhance the abstracts presented here from the 2010 Genitourinary Cancers Symposium, there are 6 “Best of the Day” interviews with leading national and international oncologists that are available in the Imedex E-Learning Center.

I hope that you have enjoyed this edition of OncoFacts and will look forward to next month’s edition.

OncoFacts™ Editor:

James Epstein, MD

Contact

4325 Alexander Drive
Alpharetta, GA 30022
Fax: +1(770) 751-7334
www.imedex.com
Email: elearning@imedex.com

For ongoing improvement, we would appreciate your comments and suggestions. Email your suggestions to: elearning@imedex.com

OncoFacts is produced by Imedex^®, LLC (Imedex). Imedex is solely responsible for this program’s content. Although Imedex attempts to ensure that the information in our programs is accurate and timely, matters and opinions discussed and/or presented with respect to clinical matters are those of the discussion participants only, and not necessarily those of Imedex. Moreover, although Imedex attempts to identify and integrate the most qualified medical professionals and key thought leaders in our programs, TO THE FULLEST EXTENT PERMITTED BY LAW, IMEDEX EXPRESSLY DISCLAIM ALL WARRANTIES, EITHER EXPRESS OR IMPLIED, STATUTORY OR OTHERWISE, INCLUDING BUT NOT LIMITED TO THE IMPLIED WARRANTIES OF MERCHANTABILITY, NON-INFRINGEMENT OF THIRD PARTIES’ RIGHTS, AND FITNESS FOR A PARTICULAR PURPOSE, WITH RESPECT TO THE CONTENT PRESENTED. IMEDEX FURTHER MAKES NO REPRESENTATIONS OR WARRANTIES ABOUT THE ACCURACY, RELIABILITY, COMPLETENESS OR TIMELINESS OF THE CONTENT OR ANY MATERIAL PRESENTED. In addition, the material presented and related discussions are not intended to be medical advice, and the presentation or discussion of such material is not intended to create and does not establish a physician-patient relationship. Medical advice of any nature should be sought from an individual’s own physician.

Neither Imedex nor any of its subsidiaries or affiliates is affiliated with or formally endorsed by a medical society.

© 2010 Imedex, LLC. All rights reserved.