The 2017 Genitourinary Cancers Symposium takes place in Orlando, FL, on February 16 – 18, and a press cast held in advance of the meeting featured 3 important abstracts, with these key findings:
Early Discontinuation of PD-1/PD-L1 Blockers May Not Compromise Efficacy
In a small study of 19 patients with metastatic renal cell carcinoma (RCC), discontinuation of anti-PD-1/PD-L1 immune checkpoint inhibitors due to side effects did not always lead to poor outcomes. The findings may challenge the current practice of continuing these drugs until (and sometimes after) the patient’s disease progresses.
Among 19 patients who initially responded to nivolumab but discontinued because of immune-related side effects, 42% had a durable response lasting for 6 months or longer, according to Rana R. McKay, MD, of the University of California San Diego School of Medicine.
“In medicine, we are constantly balancing the benefits and risks of any given treatment. This is a small study, and our findings need to be validated in a larger group of patients, but it underscores that in some cases, immunotherapy can have lasting benefits even after treatment discontinuation,” she said.
Two thirds of patients had received nivolumab as a single agent and the remainder received it in combination with other systemic treatments. The median time on immunotherapy was 5.5 months. All 19 discontinued treatment because of immune-related side effects, such as joint pain, rash, eye problems, diarrhea, and inflammation of the pituitary gland, muscle, heart, liver, pancreas, kidney or lung. Steroids were administered to 84% of patients and additional immunosuppressive agents were required for 11%. More than half the group had ongoing toxicity at the time of the analysis.
In 3 (16%) patients, the tumor progressed immediately after stopping treatment, but 8 (42%) patients had a continued response after being off treatment for at least 6 months. The remaining 8 (42%) were off treatment for 4 to 6 months or had follow-up for less than 6 months. The durable responders spent a median of 11 months on treatment and 20 months off treatment, reported Dr. McKay.
“We demonstrated that responders to anti-PD1/PD-L1 agents can have persistent clinical benefit despite treatment discontinuation for immune-related adverse events,” said Dr. McKay.
The prospective OMINIVORE study (Phase 2 study of Optimized Management of NIVOlumab based on Response) will further explore the efficacy of immunotherapy treatment discontinuation in treatment responders.
Press cast moderator and ASCO Expert Sumanta Pal, MD, reiterated the study’s message: that while the “unintended consequences of a reinvigorated immune response,” ie, immune-related adverse events, can be “serious,” patients with these side effects “can still have tangible benefit from these drugs.”
Recent Antibiotic Use May Negate Immunotherapy Benefits
In a retrospective analysis, patients with metastatic RCC who were treated with antibiotics within 1 month of starting treatment with immune checkpoint inhibitors had a significantly shorter progression-free survival, versus patients not taking antibiotics, according to French investigators.
The researchers attribute this to the ability of antibiotics to wipe out “good bacteria” in the gut, based on preclinical studies showing that certain microorganisms in the gut interact with the immune system in a way that facilitates the effect of immune checkpoint inhibitors.
The study is the first to analyze the impact of antibiotics on immune checkpoint inhibitors, and provides the first evidence of a relationship between the gut microbiome and patients’ response to immunotherapy.
The study included 80 patients with metastatic RCC enrolled in a trial of anti-PD-1/PD-L1 agents. Of these, 16 (20%) had been treated with broad-spectrum antibiotics (mostly beta-lactamases and fluoroquinolones) from baseline up to 1 month prior to the first injection.
Compared with patients not taking antibiotics, antibiotic users had significantly worse progression-free survival: 2.3 months vs 8.1 months, respectively (P< .001); their response rates to the checkpoint inhibitors were also lower.
This statistical association was maintained in a multivariate analysis that adjusted for age, gender, disease risk group, tumor burden and use of proton pump inhibitors. Antibiotic users’ risk for progression was increased more than four-fold vs non-users.
“Although it’s too early to conclude about overall survival, with median follow up of less than 6 months, there is already a negative trend in the antibody-positive group,” reported Lisa Derosa, MD, MD, a PhD candidate at the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.
Dr. Derosa suggested that the findings may be applicable to other tumor types, since antibiotics are frequently used in cancer patients in general to prevent and treat treatment-related infections. At this time, she does not recommend withholding antibiotics from patients taking checkpoint inhibitors.
Dr. Pal agreed, stating, “While Dr. Derosa’s findings are very intriguing, they were retrospectively generated and therefore are hypothesis-generating. Having said that, the observations are consistent with preclinical observations. With further prospective validation, we may gain insight as to whether the bacterial composition of the gut affects clinical outcomes, and this could help guide us in our antibiotic usage. Meanwhile, we must consider that antibiotics are used under circumstances that are medically necessary.”
In Prostate Cancer, Liquid Biopsy Reveals Potential New Treatment Targets
Analysis of cancer DNA from blood samples is yielding some new leads for potential prostate cancer treatment targets. With a commercially available liquid biopsy — which examines cell-free circulating tumor DNA (ctNDA) in the bloodstream — researchers identified new genetic mutations in prostate cancers, some of which were associated with poor prognosis.
Cell-free DNA reveals a tumor’s genetic profile, for which targeted treatments can be designed. The genetic landscape, however, changes over time, rendering some drugs ineffective because resistance develops.
If the ctDNA can identify the evolving mutations, clinicians could discontinue futile treatments and switch therapies, explained Guru Sonpavde, MD, of the University of Alabama in Birmingham.
The study included blood samples from 514 patients with metastatic castration-resistant prostate cancer (mCRPC). The test, Guardant360, examined changes in 73 cancer-related genes.
In 163 patients, researchers explored associations between DNA changes and clinical outcomes, and in 64 patients they documented genetic changes over time through serial testing.
“Almost all the patients (94%) had some change detected, and most changes were associated with worse poor outcomes,” reported Dr. Sonpavde.
Higher number of ctDNA alterations was associated with shorter time to treatment failure (P=0.026). Patients with prior treatment for mCRPC had significantly more alterations in the androgen receptor gene (AR) than untreated patients (56% vs 37%; P=0.028).
Genes most often mutated were TP53, AR, APC, and NF1. Increased copy numbers were most common with AR, MYC and BRAF; increased cancer gene copy number can lead to proliferation of proteins that drive tumor growth.
Serial testing revealed that changes in AR over time were common. Importantly, patients with these mutations also trended toward shorter remissions (P=0.053) and shorter survival time (P=0.09).
“This indicates that developing salvage therapy with agents targeting AR alterations holds promise,” commented Dr. Sonpavde.
The findings via ctDNA were consistent with changes observed through traditional tissue biopsy, suggesting that noninvasive liquid biopsy may be a viable alternative. While there are currently no approved drugs targeting the most common mutations observed, some are in clinical trials noted investigators.
Dr. Sonpavde acknowledged that a controlled, prospective clinical trial is needed to confirm that treatment based on the molecular information from ctDNA improves patient outcomes.
Dr. Pal remarked that the study offers “one of the largest clinically annotated datasets describing features of ctDNA in advanced prostate cancer, which is a simple and convenient way to assess DNA composition and can reveal new mutations that clinicians can use to personalize therapy… The development of new agents targeting the androgen receptor is a good future direction of research.”
Surgical resection is the primary treatment for patients with early-stage renal cell carcinoma (RCC) and can potentially be curative in up to 70% of cases.1 In many solid tumors, patients at high risk of recurrence are often treated with adjuvant (postsurgical) systemic therapy, with the idea being to eradicate any microscopic residual disease and thus decrease the likelihood of developing a local or metastatic recurrence. While adjuvant therapy is standard of care in many solid tumors, no adjuvant therapy has proven to increase disease-free survival in RCC; furthermore, cytokine therapies that have been studied in the adjuvant setting, such as interleukin and interferon-α, carry high levels of toxicity. As such, adjuvant therapy is rarely administered (approximately 26% of Stage III patients are administered adjuvant therapy in the U.S.2).
Nexavar® (sorafenib, Onyx / Amgen) and Sutent® (sunitinib, Pfizer) changed the treatment paradigm for advanced/metastatic RCC when they were first launched nearly a decade ago. Their widespread use in advanced RCC has also prompted debate whether they would be equally active in the adjuvant setting. While use of adjuvant therapy is minimal in RCC, among those patients who do receive an adjuvant regimen, Sutent and Nexavar are used off-label in approximately 45% of patients.2 Both agents have demonstrated increased efficacy in advanced/metastatic RCC and have good safety profiles, even for extended periods of administration, making them good candidates for adjuvant therapy. ASSURE (adjuvant sorafenib or sunitinib in unfavorable renal cell carcinoma; Eastern Cooperative Oncology Group 2805) is a Phase III trial investigating the clinical benefit and tolerability of these therapies in the adjuvant setting. ASSURE is a randomized, double-blind, multicenter trial that enrolled 1,943 patients with resected, intermediate and very high risk (as scored by UISS risk criteria1), clear cell and non-clear cell RCC who had no prior systemic therapy. Patients were randomized to one year treatment with Nexavar (400 mg twice daily, administered continuously for nine cycles), Sutent (50 mg once daily, administered for four weeks of a six-week cycle for nine cycles), or placebo. Notably, drug dosage was reduced to 400 mg Nexavar and 35 mg Sutent both given once daily as a result of adverse events and patient intolerance (see further detail below). Moreover, the sample size was increased from 1,332 patients to 1,943 patients to compensate for the dosage revision. Disease-free survival (DFS) was used as the primary endpoint, and secondary endpoints were overall survival (OS) and tolerability. Additionally, examination of angiogenic markers in tissue, blood, and urine was performed to determine their significance in predicting therapeutic benefit.
Initial results of ASSURE, reported at the 2015 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, demonstrated that Nexavar and Sutent do not improve clinical efficacy in the adjuvant setting.3 Median DFS was 5.8 years in the Nexavar and Sutent treatment arms and 6.0 years in the placebo arm (Nexavar vs. placebo HR = 0.97, p = 0.74; Sutent vs. placebo HR = 1.00, p = 0.96). Moreover, five-year DFS rates were 52.8% in the Nexavar arm (HR = 0.98), 53.8% in the Sutent arm (HR = 1.01), and 55.8% in the placebo arm. Five-year OS rates were 80.7% in the Nexavar arm (HR = 0.93), 76.9% in the Sutent arm (HR = 1.10), and 78.7% in the placebo arm.
Not only was efficacy not improved with the use of Sutent or Nexavar in the adjuvant setting, these regimens added significant toxicity. Both agents were associated with an increased incidence of hypertension, a class effect for VEGF pathway inhibitors (16% Nexavar, 16% Sutent, 4% placebo). Nexavar was also associated with increased incidence of hand-foot syndrome (15% vs. <1% placebo), rash (15% vs. <1% placebo), and diarrhea (9% vs. none placebo); Sutent was associated with increased incidence of fatigue (18% vs. 3% placebo), hand-foot syndrome (33% vs. 1% placebo), and diarrhea (10% vs. none placebo). The majority of worst degree of all event types was considered to be Grade 3 adverse events (67% Nexavar, 57% Sutent, 20% placebo), which were non-life-threatening but required medical intervention.
With the lack of even a trend to efficacy benefit and significant high-grade toxicity for both Nexavar and Sutent, the initial results of ASSURE do not support any use of these two drugs in the adjuvant setting for RCC. In light of the lack of effective adjuvant therapies for RCC, the outcomes of ASSURE will be further assessed to determine whether VEGF TKI therapy may be effective in a subset of intermediate- and very high-risk RCC patients. One point of interest that wasn’t reported in the ASCO GU presentation was the effect of dose, dose-reduction and drop-out rate on clinical efficacy. These analyses are being conducted now and hope to be reported at a future conference.
The ASSURE trial adds to the growing body of evidence that targeted therapeutics approved in the metastatic setting may not provide clinical benefit in the adjuvant setting. Other notable failures include Avastin® (bevacizumab, Genentech/Roche/Chugai) in adjuvant colon cancer4 and Erbitux® (cetuximab, Lilly/BMS/Merck KGaA) in adjuvant colon cancer.5 Not all targeted therapeutics have failed to improve efficacy in the adjuvant setting – Yervoy® (ipilimumab, BMS) improved DFS in melanoma, and Gleevec® (imatinib, Novartis) improved DFS in gastrointestinal stromal tumor – so it raises the question of whether the observed failures are due to ineffective agents or ineffective mechanisms of action. Nexavar and Sutent, while multitargeted, are considered anti-angiogenic in nature, as is Avastin; the failure of all three agents to improve DFS in the adjuvant setting suggests that anti-angiogenesis is not an effective approach to treatment and prevention of recurrence in the non-metastatic setting. In the example of Avastin in colon cancer, landmark analysis showed a clinical benefit for the period of time during which Avastin was being administered, but the benefit eroded after Avastin treatment was ceased. A similar effect appears to have occurred in the ASSURE trial; in the Kaplan Meyer curve for DFS, the Sutent and Nexavar arms were both overlapping and clearly separated from the placebo arm from approximately six months until approximately 20 months.
These trials raise the question of what the appropriate duration of therapy for an anti-angiogenic therapy in the adjuvant setting is. This issue is being explored in the ongoing SORCE study (NCT00492258), which is comparing placebo vs. Nexavar for one year or three years in resected clear cell and non-clear cell RCC patients. The ATLAS study (NCT01599754) is also exploring prolonged adjuvant therapy for another anti-angiogenic agent, Inlyta® (axitinib, Pfizer) by comparing placebo vs. Inlyta for three years in very high-risk (as scored by UISS criteria), clear cell RCC patients. These studies may provide answers to whether prolonged duration of treatment is necessary to observe a clinical benefit in these patients. However, even if these trials show a benefit with prolonged administration, the tolerability of these agents is still in question. In the meantime, the results of ASSURE support a change of treatment practice – the significant off-label use of Nexavar and Sutent (and by extension other VEGFR TKIs) in Stage I-III RCC should be ceased. With this, the level of unmet need for high-risk, early-stage RCC remains high, and determining the best treatment approach for this disease is anxiously awaited.
1. Lam JS, Shvarts O, Leppert JT, et al. “Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy.” J Urol. 2005;173:1853-62.
2. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed February 27, 2015.
3. Haas NB, Manola J, Uzzo RG, et al. “Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial.” In American Society of Clinical Oncology Genitourinary Cancers Symposium; February 28, 2015; Orlando, Florida. Abstract 403.
4. Allegra CJ, Yothers G, O’Connell MJ, et al. “Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08.” J Clin Oncol. 2011;29(1): 11-16.
5. Huang J, Nair SG, Mahoney MR, et al. “Comparison of FOLFIRI with or without cetuximab in patients with resected stage III colon cancer; NCCTG (Alliance) intergroup trial N0147.” Clin Colorect Canc. 2014;13(2): 100-109.
By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health and Stephanie Ritz, Analyst, Clinical & Scientific Assessment, Kantar Health
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