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
January 28, 2014—In a presscast held in advance of the 2014 Genitourinary Cancers Symposium (Jan. 30-Feb 1) in San Francisco, researchers reported survival improvements in genitourinary tumor types, indicating that some aspects of clinical practice could change as a result of the studies.
Enzalutamide Offers Overall Survival Benefit Prior to Chemo
In the phase III PREVAIL study, enzalutamide significantly reduced the risk of death, significantly delayed progression, produced meaningful responses in soft tissue disease, significantly delayed the time to initiating chemotherapy, and was well tolerated over an extended period of time in men with castration-resistant metastatic prostate cancer (mCRP) that progressed on androgen-deprivation therapy, according to Tomasz Beer, MD, Professor of Medicine and Deputy Director of the Knight Cancer Institute at Oregon Health and Science University.
The study enrolled 1,717 men with mCRP who had not received treatment for metastatic disease. The two primary endpoints were overall survival and radiographic progression-free survival (assessed by bone and CT scans).
Enzalutamide was associated with a 29% reduction in the risk of death (P<0.0001), and an 81% reduction in the risk of radiographic progression (P<0.0001). Treatment with enzalutamide was also associated with significantly greater responses in soft tissue disease that was measurable on imaging, 59% vs 5% for placebo.
Enzalutamide also prolonged the time before patients needed chemotherapy, which Dr. Beer called a “pragmatic measure of a real-world treatment effect.” Median time to chemotherapy was 28 months with enzalutamide, vs 10.8 months with placebo, a 65% reduction in risk and an absolute benefit of 17 months (P<0.0001).
Grade 3 and 4 adverse events occurred in 43% of the enzalutamide arm and 37% of the placebo arm. The most common adverse events with enzalutamide were back pain, fatigue, constipation and arthralgias, mostly grades 1 and 2. Only 6% of each arm discontinued due to toxicity.
“Because of these positive findings, my view is that enzalutamide provides meaningful clinical benefit” in this setting,” he said in the briefing. “If approved for this indication, it will become an important standard option for use before chemotherapy in patients with asymptomatic or minimally symptomatic advanced prostate cancer,” he went on to say.
Radiotherapy Plus Anti-Androgen Treatment Improves Long-Term Survival
In an updated analysis of the Scandinavian Prostate Cancer Group’s Study VII, the addition of radiotherapy to oral anti-androgen treatment more than halved the 10-year and 15-year prostate cancer-specific mortality rates for men with locally advanced prostate cancer, compared with anti-androgens alone.
Compared with radiotherapy alone, the combination treatment “more than doubles the 10-year survival rate and confirms that this approach should be a standard option for men with this type of prostate cancer who are expected to live at least another 10 years,” said Sophie Dorothea Fosså, Professor of Oncology at Oslo University Hospital in Norway.
The study included 875 patients with locally advanced prostate cancer who received 3 months of total androgen blockade (medical castration); half then received continuous anti-androgen therapy while the other half received continuous anti-androgens plus radiotherapy (70-74 Gy). They were followed for a median of 10.7 years.
Fosså noted that the radiation dose is higher than is typically used in the United States, which may help explain the benefit observed in this study.
The cumulative prostate cancer-specific mortality rate at 10 years was 8% with the combination vs 19% with hormonal therapy alone, a 65% reduction, and at 15 years was 12% and 31%, respectively.
The overall mortality rate was 26% vs 35%, respectively, at 10 years, and 43% and 57%, respectively, at 15 years, she reported. She noted that the 10-year prostate cancer-specific mortality rate of 8% is comparable to results after prostatectomy in comparable patients.
“In these patients, the combination of radiotherapy and hormones may be considered a standard curative treatment option,” she suggested.
Anti-Hypertensive Agent Improves Survival in RCC
A retrospective analysis of patients with metastatic renal cell carcinoma (RCC) found that patients who received an angiotensin system inhibitor (ASI) had improved survival, compared with patients not treated with these agents. When patients also received an agent targeting the vascular endothelial growth factor (VEGF) pathway, survival was further improved, according to Rana McKay, MD, an oncology fellow at Dana Farber Cancer Institute, Boston.
Dr. McKay said the results support the use of ASIs for metastatic RCC patients who are hypertensive and lack contraindications for their use.
The findings came from an analysis of 4,736 patients treated in phase II and III clinical trials. Median overall survival for patients receiving ASIs (n=1,487) was 26.7 months, compared with 17.05 months for those not using ASIs (n=3,249) (HR 1.213; P=0.0009).
Further analysis showed that overall survival was improved in ASI users vs non-users, but was only statistically significant in patients also receiving a VEGF-targeted agent. For this group, median overall survival was 31.12 months versus 21.94 months for non-users (HR 1.380; P=0.0003).
Differences were not significant for users of mTOR-targeted agents or interferon-alpha.
One in Five Cancer Clinical Trials Never Completed
An analysis of cancer clinical trials registered on the web site Clinicaltrials.gov showed that about 20% of trials fail to complete, for reasons unrelated to a drug’s efficacy or toxicity.
Matthew Galsky, MD, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York, reported the findings from an analysis of trials registered on the web site between 2005 and 2011.
He noted, “Trials that are initiated, but fail to complete—ie, close without enrolling the intended number of subjects—represent an extreme example of inefficiency.”
Dr. Galsky and colleagues found that of 7,776 phase II or III interventional trials in adult cancer patients, approximately 20% failed to complete for reasons unrelated to efficacy or toxicity. The main reason was failure to accrue.
Other reasons included inadequate funding, cancellation by the sponsor, and departure of the principal investigator. Fewer than 20% closed because of lack of efficacy or excessive toxicity, and these were excluded from the analysis.
“These failures represent important barriers to progress in cancer care,” he said.
Dr. Galsky commented that this research is “not an indictment of any particular stakeholder,” instead, “we want to hold up a mirror” for the entire clinical trials system. “Clearly, there’s work to do,” he said.
by Caroline Helwick
Clinically speaking, hepatocellular carcinoma (HCC) is a particularly challenging disease. Surgery remains the only curative strategy for patients with HCC, however not all patients are eligible for surgery. The approval of Nexavar® (sorafenib, Bayer/Onyx/Amgen) revolutionized HCC, providing a targeted therapy option for patients with HCC and an advance over de facto standard doxorubicin. The enthusiasm for Nexavar is dampened by the fact that not all patients may be eligible for Nexavar treatment due to poor liver function, and options remain limited for patients whose disease progresses. Since the introduction of Nexavar, other targeted therapies have attempted to carve a place in the HCC treatment landscape, either as frontline agents or in the relapsed setting, only to be met with failure.
Recent pivotal trial failures include: Sutent® (sunitinib, Pfizer) in comparison with Nexavar in first-line;1 brivanib compared with Nexavar in first-line2 and in Nexavar-refractory patients;3 and most recently Afinitor® (everolimus, Novartis) failed to demonstrate efficacy in Nexavar-refractory HCC patients.4 Despite multiple failures, there is a long list of agents that are currently in active clinical development either in Phase II or Phase III trials, with most agents aiming for the Nexavar-refractory population. Agents currently in pivotal trials in Nexavar-refractory patients include ADI-PEG20 (Polaris Group), Cometriq® (cabozantinib, Exelixis), ramucirumab (Eli Lilly), and Stivarga® (regorafenib, Onyx/Amgen), as well as tivantinib (Arqule/Daiichi Sankyo) that is being studied in a subpopulation of patients with MET overexpression.
Into this matrix enters LY2157299, a novel transforming growth factor-beta receptor 1 (TGF-β1) kinase inhibitor that Eli Lily is developing in HCC. Elevated TGF-β1signaling promotes liver fibrosis and progression to HCC; hence targeting TGF-β signaling has been proposed as a unique approach in HCC treatment. While limited data is available with LY2157299, this agent prevented HCC cancer cell migration on extracellular matrix substrates in cell culture studies.5 Given the potential importance of this pathway in HCC and some preliminary evidence that inhibition of this pathway can inhibit certain processes in HCC, Eli Lilly is evaluating this compound in an ongoing Phase II study. The trial is evaluating LY2157299 in patients ineligible for Nexavar therapy or who have progressed on Nexavar. While the trial is still recruiting, interim results were presented6 at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium on Friday, January 17, 2014. The study accrued 109 patients who were randomized to two arms: Arm A LY2157299 at 160 mg/day and Arm B LY2157299 at 300 mg/day. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-β, and e-cadherin). Serum AFP was used as a surrogate marker for clinical efficacy and patients in whom AFP levels decreased greater than 20% compared to baseline were considered “AFP responders.” Of the eligible patients accrued, about 80% were Nexavar-pretreated and 50% had AFP levels greater than 400 ng/ml at baseline. The median TTP was 12.0 weeks in Nexavar-refractory patients (90% CI: 6.6-12.6) and 18.3 weeks in Nexavar-naïve patients (90% CI: 6.6-42.4). About one-quarter of the patients achieved more than a 20% decrease in AFP levels and were categorized as AFP-responders. The drug was very well-tolerated, with the most common grade 3/4 toxicities being neutropenia (2.7%) and fatigue (1.8%). Perhaps the most exciting piece of data from this study was the increase in median OS in the AFP responder population compared to AFP-non-responders (93.1 weeks versus 29.6 weeks; p=0.00006). In contrast, median OS in the entire population was 8.3 mos (36 weeks). Given that Nexavar achieves an OS of about 10 months and given that not all patients can tolerate Nexavar, this appears to be a niche positioning opportunity for Eli Lilly.
Although this study is very promising, there are a couple of caveats. Key amongst them is the use of AFP as a biomarker. Decreases in AFP levels have been shown to be clinically useful in monitoring tumor response in HCC patients; however, AFP detection is also known to be a poorly reliable marker, particularly in small tumors.7 This may present a challenge in metastatic disease or on small tumors that progress very slowly. Whether AFP is the most appropriate biomarker to use in this context and whether this is an appropriate biomarker to support approval down the line is not known – all biomarkers approved to-date focus on patient selection based on baseline presence of the biomarker; this would pave new ground as a biomarker of response post-therapy, and perhaps would be more useful in guiding decisions of whether to continue treating patients with the drug as opposed to guiding decisions of whether to initiate therapy with the drug. In addition, whether the inhibitor is truly inhibiting the TGF-βpathway is not known, as downstream targets such as phosphor-Smads have not yet been evaluated. The phosphorylation of Smad protein plays an important role in TGF-β signaling and activates a nuclear transduction protein.
So where does LY2157299 stand in terms of novel agents in HCC? Clearly, it is too early to determine how this compound will fit into the overall picture of HCC therapy. The table below provides a preview of the clinical efficacy of LY2157299 in comparison to the key agents in development in Nexavar-refractory patients.
Table 1: Efficacy Outcomes in Nexavar-pretreated HCC
In favor of LY2157299 are its manageable toxicity profile and the fact that it targets a novel pathway. However, the demonstrated efficacy benefit in the general population is not striking compared to the other agents currently in development in the same population. The OS and TTP observed with LY2157299 in AFP responders are particularly intriguing; however, whether the test is appropriate or whether AFP level is an appropriate marker for response remains a concern. While the study is promising, we will have to wait until the data mature and see how this plays out in a larger Phase III trial.
By Neesha Suvarna, PhD, Consultant, Kantar Health and Len Kusdra, Analyst, Kantar Health
January 14, 2014 — The 2014 ASCO Gastrointestinal (GI) Symposium will run from January 16-18, 2014, at the Moscone Center West in San Francisco, CA. More than 2500 medical, surgical, and radiologic specialists will attend and learn about the latest translational science and new approaches to diagnosis and management of GI cancers.
A pre-meeting Presscast featured 5 important studies: 3 in difficult-to-treat cancers and 2 focusing on more convenient treatments and improved quality of life.
Anti-Angiogenesis with Ramucirumab
Second-line treatment with the combination of ramucirumab (an anti-angiogenesis inhibitor) plus paclitaxel increased overall survival (OS) by more than 2 months in patients with metastatic gastroesophageal junction (GEJ) and gastric carcinoma, according to results of the Phase III RAINBOW trial. This trial comes on the heels of the REGARD trial, showing that single-agent ramucirumab improved progression-free survival (PFS) in this setting.
Median OS is 4-5 months with currently available second-line therapies. In RAINBOW, ramucirumab plus paclitaxel achieved a median OS of 9.6 months versus 7.4 months with paclitaxel (P=.016). Median PFS was 4.4 months for the combination versus 2.9 months with paclitaxel alone (P=.016).
“These are astonishingly good results in this patient population. The improvement in survival was not only statistically significant, but clinically meaningful as well. The rate of tumor progression was reduced by 36%, and 6-month and 9-month PFS almost doubled [with ramucirumab],” stated lead author Hansjochen Wilke, MD, Kliniken Essen-Mitte, in Essen, Germany.
RAINBOW, the largest gastric cancer second-line therapy trial conducted to date, enrolled 665 patients who progressed within 4 months of standard first-line platinum- and fluoropyrimidine-based combination chemotherapy. Patients were treated until disease progression, unacceptable toxicity, or death.
Currently, only about 30% of patients with advanced gastric cancer receive second-line therapy in the U.S. compared with about 80% in Japan. “We expect that more people will be treated with second–line chemotherapy with this effective new drug,” said Dr. Wilke.
Updated results of a Phase II randomized trial found that a double hit with 2 vaccines (GVAX followed by CRS-207) markedly improved OS in patients with metastatic pancreatic ductal carcinoma compared to GVAX alone. Median OS was 6.1 months with the combination versus 3.9 months with GVAX alone (P=.0343).
After 1 year, about 24% of patients were alive in the combination arm versus 12% of those in the GVAX-alone arm. Among patients who received 2 doses of GVAX and at least 1 dose of CRS-207, median OS was 9.7 months versus 4.6 months, respectively, (the protocol called for 2 doses of GVAX and 4 doses of CRS-207).
Side effects were related to mode of administration (sub dermal or intra venous) and resolved quickly.
The study enrolled 90 patients with metastatic pancreatic cancer who failed or refused chemotherapy.
“This is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer. This is just a first step, and we plan to take this approach further,” stated lead author Dung T. Le, MD, Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD.
“This strategy extends survival without encountering the effects of chemotherapy,” stated Smitha Krishnamurthi, MD, Case Western Reserve University, Ohio, who moderated the Presscast.
An additional 3-arm study is being planned to evaluate the combination compared with CRS-207.
CAPTEM (Capecitabine and temozolomide)
The combination of capecitabine and temozolomide (CAPTEM) achieved durable responses and extended PFS in 95% of patients with neuroendocrine tumors (NET) that progressed on standard high-dose octreotide. Responders included patients with carcinoid NET, which are typically chemoresistant.
A few patients in this small study were able to get off their respirators and resume normal activities, and the remissions are long lasting, said lead author Robert L. Fine, Columbia University Medical Center, New York City.
“New treatments are sorely needed for this disease,” said Dr. Fine.
The study included 28 patients with various subtypes of NET. CAPTEM achieved tumor shrinkage in 43% of patients and stopped tumor growth in 54%. High response rates were observed in carcinoid and pituitary NET, typically very difficult to treat tumor subtypes.
Among 12% of those with carcinoid tumors, 41% had tumor shrinkage; the typical response to chemotherapy in this subgroup is 0%-4%. Among the 4 patients with pituitary tumors, CAPTEM achieved 2 complete remissions, 1 partial remission (75% reduction in tumor size), and 1 had stable disease for 5 years.
The most recent data capture shows that median PFS approaches 30 months and more than 4 years for 25% of patients. Median OS is longer than 25 months.
Toxicities were minimal, said Dr. Fine.
The combination versus temozolomide alone is now being studied in a cooperative group trial.
“Although small and not randomized, this trial is of great interest because CAPTEM achieved responses in patients we consider chemoresistant,” said Dr. Krishnamurthi.
Oral capecitabine achieved equivalent outcomes as standard continuous infusional 5-FU when combined with neoadjuvant radiation in patients with stage II or III rectal cancer, according to mature results of NSAPB R-04. The study also found that oxaliplatin is of no additional benefit when added to either drug and is associated with increased overall toxicity.
The study randomized 1608 patients who were receiving 5 weeks of neoadjuvant radiation therapy to 1 of 4 arms: 5-FU; 5-FU + oxaliplatin; capecitabine; capecitabine + oxaliplatin. Results showed no significant differences in loco-regional control rates and other 5-year outcomes, including disease-free survival and OS, among all 4 treatment arms.
“This study shows you can use an oral drug, capecitabine, or continuous infusional 5-FU plus radiation, with indistinguishable outcomes. The same was true for oxaliplatin, but the side effects, especially increased grade 3 and 4 diarrhea, suggest that this drug should not be used in combination with radiotherapy in the preoperative rectal cancer setting,” stated lead author Carmen J. Allegra, MD, University of Florida in Gainesville.
“Doctors should be reassured that they are not giving less effective therapy if they prescribe capecitabine. Oral capecitabine is certainly far more convenient for patients than placing an intravenous port for 5-FU and wearing a pump on their belts for 5 weeks.”
Extended RAS Testing
A retrospective analysis of a large Phase III study supports the use of extended KRAS testing in patients with metastatic colorectal cancer (mCRC) to identify subgroups that should be treated with panitumumab and other EGFR inhibitors. The study showed that tumors that contain RAS mutations beyond KRAS exon 2 are unlikely to benefit from the addition of panitumumab to second-line FOLFIRI chemotherapy.
“Testing for RAS mutations will allow doctors to better select patients and only recommend panitumumab treatment to those most likely to benefit. These results confirm that it is RAS status that matters, not just KRAS, when determining if panitumumab therapy could be beneficial. These findings will spare patients with a RAS mutation the costs and side effects of a treatment that will not improve their outcomes,” stated lead author Marc Peeters, MD, PhD, Antwerp University Hospital, Edegem, Belgium.
The study was based on tumor samples from 1186 patients enrolled in a large, international Phase III study evaluating the addition of panitumumab to FOLFIRI as second-line therapy.
Forty-five percent of the patient population had mutated KRAS exon 2. Extended RAS testing revealed mutations that predicted for response to panitumumab in another 18%.
Among patients treated with both panitumumab and FOLFIRI, median OS and median PFS were improved in those with wild-type RAS tumors versus those with RAS mutations: median OS was 16.2 months versus 11.8 months, respectively, and median PFS was 6.4 months versus 4.8 months, respectively. The addition of panitumumab to FOLFIRI was of no added survival benefit versus FOLFIRI alone in those who received panitumumab plus chemotherapy: median OS 11.8 months versus 11.1 months, respectively; median PFS was 4.8 months versus 4.0 months, respectively.
“These findings support extended RAS testing as standard of care for metastatic CRC to identify patients who will benefit from panitumumab,” said Dr. Krishnamurthi.
By Alice Goodman