Experts from all over the world are gathering to tackle challenges in managing prostate, kidney, bladder, testicular, and other genitourinary (GU) cancers at the 2015 Genitourinary Cancers Symposium in Orlando, Florida, February 25-28th.
A pre-meeting Presscast gave a sneak preview of five important studies to be presented at the meeting.
AR-V7 Potential Marker for Chemotherapy Sensitivity
A small study of 37 men found that an androgen receptor (AR) abnormality called AR-V7 appears to predict for sensitivity to taxanes (docetaxel and cabazitaxel) in men with metastatic castration-resistant prostate cancer (CRPC). This study comes on the heels of a previous study by the same group showing that the presence of AR-V7 in circulating tumor cells predicts resistance to hormone therapy with enzalutamide and abiraterone.
The field of prostate cancer lags behind breast cancer and other cancers where predictive markers have been identified. Results of the two studies by this group, taken together, suggest that AR-V7 positive patients with metastatic CRPC should be offered chemotherapy as initial therapy, rather than AR-directed hormone therapy, while those who are AR-V7 negative can be safely treated with either regimen.
“We urgently need markers which predict which therapies are going to be effective and which will not … in individual patients with prostate cancer. AR-V7 testing may be extremely valuable in guiding treatment decisions for men with hormone-resistant disease in the near future,” said lead author Emmanuel Antonarakis, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, MD. He noted that as yet there is no commercially available CLIA-certified test for AR-V7, “but we and others are working on that.”
Based on these data, which need validation in a prospective, multicenter trial, Dr. Antonarakis said that the test for AR-V7 appears to be of greater utility for positive patients. The AR-V7 abnormality is thought to occur in about one third of patients with CRPC.
Testicular Cancer Linked to Aggressive Prostate Cancer
A history of testicular cancer increases the likelihood of developing intermediate- and high-risk prostate cancer, according to a case-control study of about 180,000 men. By age 80, the study showed that prostate cancer developed in 12.6% of men with a history of testicular cancer compared with 2.8% of those with no such history. The incidence of intermediate- or high-risk prostate cancer was 5.8% versus 1.1%, respectively.
Overall, a history of testicular cancer was associated with a 4.7 times higher risk of prostate cancer and 5.2 times higher risk of intermediate- or high-risk disease.
“This study should alert men with a history of testicular cancer [and other risk factors for prostate cancer] to have a discussion with their doctor about assessment of risk of prostate cancer,” said senior study author Mohummad Minhaj Siddiqui, MD, University of Maryland School of Medicine and director of urologic robotic surgery at the University of Maryland, Marlene and Stewart Greenebaum Cancer Center in Baltimore, MD.
Dr. Siddiqui noted that the link between a history of testicular cancer and the development of prostate cancer has been previously reported, but the new finding is the increased risk of intermediate- and high-risk prostate cancer. He said that further research is needed on the biologic link between these two diseases.
The absolute risk of developing intermediate- or high-risk prostate cancer was low: 95% of men who have had testicular cancer will not develop it, said Dr. Siddiqui.
The study was based on SEER (Surveillance, Epidemiology, and End Results) data that included 32,435 men with a history of testicular cancer and 147,044 men with a history of melanoma. Melanoma was chosen as the control group, because it has no known association with prostate cancer.
Intermediate-Risk Prostate Cancer and Active Surveillance
Patients with intermediate-risk (IR) prostate cancer fare far worse than those with low-risk prostate cancer when managed with active surveillance. In fact, IR patients managed with active surveillance had almost a four times higher risk of prostate cancer-specific death over 15 years compared with low-risk patients. These were the findings of the first study to analyze long-term outcomes of patients with IR prostate cancer managed by active surveillance.
“This study validates active surveillance for low-risk patients with prostate cancer. We were surprised by the greater risk of prostate cancer death in the IR patients assigned to active surveillance,” stated presenting author, D. Andrew Loblaw, MD, Sunnybrook Health Sciences Center in Toronto, Canada.
Data were collected prospectively on 945 patients: 237 with IR and 708 with low-risk prostate cancer managed with active surveillance between 1995 and 2013 at Sunnybrook Health Sciences Center. Radiation or surgery was offered for disease progression, and 86 IR patients were treated.
Ten-year and 15-year overall survival (OS) rates were 68.4% and 50.3% for IR patients compared with 83.6% and 68.8% for low-risk patients. Dr. Loblaw noted that 60% of the IR patients were older than age 70, and men in the IR category in general had short life expectancies due to other comorbidities.
Overall, IR patients had a 3.75 times higher risk of prostate cancer-specific death at 15 years compared with low-risk patients (11.5% versus 3.7%, respectively).
Charles Ryan, MD, moderator of the Presscast, said that further sub-categorization of IR patients based on molecular and/or clinical markers is an ongoing area of study. Dr. Ryan is an ASCO Expert and GU News Planning Team Member.
“We think there may be a subgroup of IR patients out there who may be safely managed by active surveillance,” Dr. Loblaw said. “Further research is needed to better characterize those patients.”
PSA Screening for Prostate Cancer Revisited?
Between 2009 and 2011, the incidence of higher-risk prostate cancer has increased by almost 6%, leading to an estimated 1400 additional prostate cancer-specific deaths 10 years later, according to a retrospective study of 87,562 men diagnosed with prostate cancer between January 2005 and June 2013. The authors state that further research is needed to confirm these findings.
The year 2011 corresponds to the U.S. Preventive Services Task Force (USPSTF) draft recommendation against PSA screening for all men in the general population. One interpretation of the study findings is that implementing these recommendations led to identification of prostate cancer at a more advanced stage.
“Our study is the first to measure changes in prostate cancer presentation in the period following the USPSTF PSA screening recommendations. Given the findings of our analysis in this time frame, men who are at increased risk for prostate cancer, especially those with a family history of prostate cancer, should consider talking with their doctor about PSA screening,” said lead author Timothy F. Schultheiss, PhD, City of Hope, Duarte, CA.
“We can only speculate about whether the USPSTF recommendations are responsible [for the increase in higher risk cases being diagnosed], but we believe that the USPSTF might reconsider their recommendation,” he further stated.
Dr. Ryan said: “This study adds to the ongoing debate about PSA screening and underscores the importance of reconsidering guidelines.”
Don’t Change Standard of Care for Locally Advanced Kidney Cancer
Adjuvant sorafenib and sunitinib did not improve disease-free survival (DFS) in patients with locally advanced kidney cancer who are at high risk of recurrence. These results of the first and largest study on the efficacy of adjuvant VEGF inhibitors (sorafenib and sunitinib) in this setting suggest that the standard of care for these patients should remain close observation.
“No one could be more disappointed in these results than me, except for the patients with kidney cancer. Even though these drugs provide benefit in the metastatic setting, they did not reduce disease recurrence in the adjuvant setting, and they did increase side effects,” said lead author Naomi B. Hass, MD, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA.
Ongoing analysis of tumor specimens collected during the trial may help identify subsets of patients who might benefit from VEGF inhibitors in the adjuvant setting, she said.
The study included 1943 patients who underwent surgery and were deemed high risk for recurrence based on tumor size, grade, and lymph node involvement. Patients were randomized to receive sorafenib, sunitinib, or placebo for 1 year.
Interim analysis revealed similar rates of recurrence in all three groups (around 40%) and similar rates of DFS (5.6 – 5.7 years). Final analysis of recurrence and survival will be presented in the future.
Other adjuvant trials of axitinib (a VEGF inhibitor) and everolimus (mTOR inhibitor) are accruing patients, and adjuvant trials of immunotherapy and other targeted approaches are under development.
“The fact that this is a negative trial no way diminishes its importance. Tyrosine kinase inhibitors [VEGF inhibitors] may not be as effective as chemotherapy in the adjuvant treatment of solid tumors,” Dr. Ryan stated. “This study supports my current practice of not using these drugs in the adjuvant setting.”
By Alice Goodman
ABSTRACT NUMBERS FOR REFERENCE:
• AR-V7. [Abstract 138]
• Testicular cancer and prostate cancer. [Abstract 177]
• Active surveillance of intermediate-risk prostate cancer [Abstract 163]
• Increase in higher-risk prostate cancers following USPSTF 2011 recommendations for PSA screening. [Abstract 143]
• Adjuvant sorafenib and sunitinib for locally advanced kidney cancer. [Abstract 403]
Prostate cancer is the most common cancer in men and the second most common cause of cancer deaths in men in the United States. The incident population of prostate cancer in the United States was above 200,000 patients in 2013.1 The rate of prostate cancer growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone.
Perhaps the most important recent advances in treatment of prostate cancer are the development and approvals of the next generation anti-androgens, Xtandi® (enzalutamide, Medivation/Astellas), FDA approved in August 2012 for treatment of metastatic castrate-resistant prostate cancer (mCRPC) in the post-docetaxel setting, and Zytiga® (abiraterone, Johnson & Johnson), FDA-approved in April 2011 in the post-docetaxel setting and subsequently approved in December 2012 to include use in the chemotherapy-naïve mCRPC setting. Approval of these two next-generation anti-androgens set the scene for an epic battle for market share between these agents.
Impressive results from the international Phase III PREVAIL study were presented Thursday January 30, 2014, at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium by Dr. Tomasz Beer.2 PREVAIL, a randomized, placebo-controlled Phase III trial was designed to evaluate safety and efficacy of Xtandi versus placebo in patients with mCRPC. A total of 1,717 men who were asymptomatic or mildly symptomatic and chemotherapy-naïve were randomized to receive either Xtandi (n=872) or placebo (n=845). Co-primary endpoints were overall survival and radiographic progression-free survival (rPFS). The trial design included one planned interim analysis at approximately 516 events. The Independent Data Monitoring Committee analyzed the data following 540 deaths and reported significant benefits in overall survival and rPFS for patients in the Xtandi arm. Following this interim analysis, PREVAIL was halted, unblinded, and patients in the placebo arm were offered treatment with Xtandi.
The median duration of treatment was more than three-fold longer for the Xtandi arm at 16.6 months versus 4.6 months for the control arm. rPFS was estimated at 13.8 months for the Xtandi arm versus 3.9 months for the placebo arm (HR=0.186; p < 0.0001) and this benefit favored Xtandi across all subgroups of patients (including performance status, age, geographic region, and presence of visceral disease). Treatment with Xtandi also provided a significant 29% improvement the risk of death, with an estimated 32.4 months median overall survival in the Xtandi arm compared with an estimated 30.2 months for the placebo arm (HR=0.706; p<0.0001). This improvement in overall survival came despite the fact that more patients from the placebo arm (70.3%) received at least one subsequent life-extending therapy compared with just 40.3% of patients in the Xtandi arm. Again, the survival advantage provided by Xtandi was consistent across all patient subgroups. Xtandi therapy yielded an objective response rate of 58.8%, including a complete response rate of 19.7%, compared with an objective response rate of only 4.9% and a 1% complete response rate in the placebo arm. Xtandi also delayed the median time to initiation of chemotherapy by 17 months (28.0 months versus 10.8 months). Xtandi was well tolerated in this trial, with the most common adverse events reported as fatigue, back pain, constipation and arthralgia, most of which were low grade. Other adverse events of interest that were slightly more prevalent in the Xtandi arm included cardiac adverse events, and hypertension, again, mostly low grade. Seizures were reported in one patient from each treatment arm.
With strongly positive results from PREVAIL in hand, Medivation and Astellas will waste no time with their regulatory submissions to expand the label of Xtandi to include chemotherapy naïve mCRPC. Upon approval, Xtandi will join Zytiga and Provenge® (sipuleucel-T, Dendreon) as the only approved agents to treat mCRPC prior to docetaxel therapy. How physicians will choose which drug to use initially, and the ideal sequence of therapies over the course of the disease, is currently one of the most asked questions in the prostate cancer field. If we look strictly at clinical outcomes in the two pivotal Phase III trials in chemotherapy-naïve mCRPC (keeping in mind the usual caveats about cross-trial comparisons), both Xtandi and Zytiga significantly improve rPFS (with potentially stronger benefit in the Xtandi trial) but slight differences exist with regard to impact on overall survival ― Zytiga offers a 5.2 month OS benefit that failed to reach statistical significance,3 while Xtandi offers a 2.2 month OS benefit that did reach statistical significance. Which of these outcomes will prove more meaningful and convincing to physicians and patients who are weighing their options between multiple effective agents, and what other factors will come into play in such decisions? With both drugs projected to be blockbusters, this truly is the billion dollar question. Other factors to be considered include:
There remain a lot of unknowns with regard to the future treatment paradigms for mCRPC. But one thing remains certain: the pace of development, level of competition, and clinical improvements in prostate cancer are growing by leaps and bounds, and the patients will reap the greatest rewards.
1 Kantar Health CancerMPact® United States Patient Metrics, accessed January 30, 2014.
2 Beer TM, et al., Abstract LBA1, ASCO GU Symposium 2014.
3 Zytiga FDA label, accessed January 30, 2014.
By: Stephanie Hawthorne, Ph.D., Director, Clinical & Scientific Assessment, Kantar Health and Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health
In recent years the field of prostate cancer has undergone significant evolution with the introduction of newer, better-tolerated treatment options. The introduction of the first therapeutic cancer vaccine (Provenge, Dendreon) sparked the idea of treating metastatic castrate-resistant prostate cancer (mCRPC) patients who weren’t symptomatic. This was followed by the advent of novel hormonal therapies being used in the post-chemotherapy setting, which challenged the previous notion that these patients were hormone-insensitive. Most recently, we’re witnessing the influx of these novel hormonal therapies into the pre-chemotherapy setting. However, one area that has remained stable over the years is the treatment paradigm for newly symptomatic mCRPC. The TAX327 trial was key in establishing docetaxel plus prednisone as the “gold standard” for patients with mCRPC. For nearly a decade it’s been a foregone conclusion that docetaxel is the best treatment option for these patients, and to improve upon outcomes in the first-line setting we need to develop new regimens that build on the docetaxel foundation. In the era of targeted therapy, it’s not surprising that several targeted agents have been investigated to explore additive benefits to this regimen with the goal of improving survival beyond the 19 months that the docetaxel/prednisone regimen offers (Tannock, 2004). However, it is saddening to observe that front-line mCRPC has become a graveyard for novel therapies, including atrasentan (AstraZeneca), Avastin® (bevacizumab, Roche/Genentech/Chugai), Revlimid® (lenalidomide, Celgene), Zaltrap® (ziv-aflibercept, Regeneron/Sanofi), and zibotentan (ZD4054, AstraZeneca). Each of these drugs demonstrated early promise of activity, but each has attempted and failed to improve upon the bar that docetaxel set for overall survival. Now one more promising targeted agent has met with the same fate: Sprycel® (dasatinib, Bristol-Myers Squibb). The results from the pivotal READY trial were reported Thursday at the American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium in Orlando, Florida.
The trial (NCT00744497) evaluated whether Sprycel improved survival when added to the docetaxel/prednisone regimen as first-line therapy in mCRPC patients. The study accrued 1,522 patients who were randomized 1:1 to Sprycel/docetaxel/prednisone or docetaxel/prednisone. Disappointingly, the study failed to achieve an improvement in median overall survival (mOS): the curves for the two arms were overlapping (mOS 21.2 months in placebo/docetaxel arm versus 21.5 months in Sprycel/docetaxel/prednisone arm; HR 0.99, p=0.9009). Subset analysis by age, EGOG status, bone metastasis or PSA progression also failed to demonstrate any difference in mOS between the two arms. There was no difference in median progression-free survival (mPFS) in the Sprycel/docetaxel/prednisone arm versus placebo/docetaxel/prednisone arm (11.8 versus 11.1 months; HR 0.92, p=0.2164). A modest delay in skeletal-related events was observed in the Sprycel arm, which was not entirely surprising considering the Src relation to osteoclasts.
The efficacy of placebo/docetaxel/prednisone arm in the READY trial is strikingly similar to that observed in the placebo/docetaxel/prednisone arm from the Zaltrap pivotal trial (VENICE) (Tannock, Abstract 13, ASCO GI 2013). The VENICE trial was previously reported to have failed via press release, but this was the first time that complete data was reported. In the VENICE trial, Zaltrap plus docetaxel/prednisone achieved a mOS of 22.1 months, which was not significantly different (p=0.38) compared to 21.2 months mOS in the placebo/docetaxel/prednisone arms. There were no differences in mPFS or PSA responses between the Zaltrap/docetaxel/prednisone and placebo/docetaxel/prednisone arms (mPFS: 6.9 versus 6.2 months; PSA: 68.6% versus 63.5%). Additionally, Zaltrap added some toxicities, including gastrointestinal perforations, hypertension, infections and respiratory disorders, that led to shorter duration of treatment.
Mechanistically (Src kinase inhibition) and preclinical studies (synergism with docetaxel) laid a very solid foundation for the investigation of Sprycel in prostate cancer. However, the transition for Sprycel into clinics was based on mediocre Phase I/II results. In that study, the addition of Sprycel to docetaxel demonstrated an improvement in partial tumor response (60%) and superior PSA decline (57%) when compared with historical controls (Araujo, Cancer 2012, 118: 63-21). The biggest criticism of the READY trial was launch of a large, 1,500-patient Phase III trial on the basis of efficacy observed in a single-arm (less than 50 patients) Phase II study with no clear PFS or survival benefit. The caveats of comparing single-arm studies with historical data becomes more apparent when comparing the differences in OS benefit of the control arms in the READY and VENICE pivotal trials (mOS: 21.2 months) with that observed in the TAX327 trial (mOS: 19.2 months).
Is there any hope left for targeted therapies or novel chemotherapies hoping to improve upon the activity of docetaxel in first-line mCRPC? A quick review of history (eight failed agents) and current landscape (two in pivotal trials) might suggest “Very Slim.” Currently two agents are in pivotal clinical trials for chemotherapy-naïve symptomatic mCRPC. Custirsen (OGX-011, Oncogenex/Teva) is an antisense oligonucleotide that is currently in a Phase III trial (SYNERGY) in combination with docetaxel/prednisone versus docetaxel/prednisone. The primary endpoint is OS, and the trial is expected to report results by the end of 2013. The pivotal trial was initiated based on data from a randomized Phase II trial in which custirsen/docetaxel/prednisone failed to achieve the primary endpoint of improved PSA decline rate or improved response rate. However, custirsen/docetaxel/prednisone improved OS (23.8 months versus 16.9 months), and a trend to improved PFS was observed (7.3 versus 6.1 months) compared to docetaxel/prednisone. With the caveat of cross-trial comparison, the efficacy of the placebo arm in this Phase II trial compares closely to that from TAK327 trial but is much lower than that observed with docetaxel-alone arms in the VENICE and READY trials, leading to some concerns that SYNERGY could meet with the same fate.
The other agent in a pivotal trial in this setting is Jevtana® (cabazitaxel, Sanofi), which is a taxane derivative that is currently approved for docetaxel-pretreated mCRPC patients. Jevtana is being investigated in the Phase III FIRSTANA trial, comparing docetaxel plus prednisone versus Jevtana plus prednisone in first-line mCRPC. The endpoint of this trial is OS, and the trial will report by the end of 2013. To date, Jevtana has not been explored in a head-to-head trial with docetaxel, and the only available results are from docetaxel-refractory patients, where Jevtana/prednisone achieved mOS of 15.1 months and mPFS of 2.8 months (deBono, Lancet 2010; 1147-1154). It would be interesting to see whether Jevtana will be able to demonstrate superiority to docetaxel in the front-line setting and manage to maintain a decent toxicity profile with few discontinuations due to toxicity.
The mCRPC market appears to be on a trajectory toward a relinquishment to novel hormonal agents and a regression of chemotherapy and other targeted therapies to later lines. If Jevtana manages to supersede docetaxel, it may only be a marginal improvement in this field, with a swap of one taxane for another. As the only targeted agent left in late-stage development seeking to improve upon the efficacy of docetaxel, custirsen could be the only hope left to rejuvenate interest in targeted therapy plus chemotherapy combinations, keeping alive the complex interplay between hormones and chemotherapy in the management of mCRPC.
By: Neesha Suvarna, PhD, Consultant, Kantar Health