ASCO 2017: News in Genitourinary Cancer - High Risk Prostate Cancer

ASCO 2017. LBA 3. LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.

Karim Fizazi et al.

Results:

 

Conclusions: Early use of AA+P added to ADT in pts with high-risk mHNPC yielded significantly improved OS, rPFS, and all secondary end points vs ADT+PBOs alone. ADT+AA+P had a favorable risk/benefit ratio and supports early intervention with AA+P in newly diagnosed, high-risk mHNPC. 


ASCO 2017. LBA 5003. Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE

Nicholas D. James et al.

Results: 1,917 pts were contemporaneously randomized to these arms (Nov 2011- Jan 2014). Groups were balanced: median age 67yrs; 52% metastatic, 20% N+/X M0, 28% N0M0; 95% newly-diagnosed; median PSA 53ng/ml. Median follow-up was 40m. There were 262 control arm deaths (82% PCa). The adjusted HR = 0.63 (95% CI 0.52-0.76; p=0.115x10-7; 184 deaths) for SOC+Abi vs SOC, with 3yr OS improved from 76% to 83%. There were 535 control arm FFS events; the adjusted HR = 0.29 (95% CI 0.25-0.34; p = 0.377x10-63, 248 FFS events) for SOC+Abi vs SOC. Grade 3 & 4 adverse events were seen in 29% & 3% SOC, 41% & 5% SOC+Abi; Grade 5: 3 & 9 (1 & 2 related). 

Conclusions: The results show a clinically & statistically significant effect on overall survival & failure-free survival from adding abiraterone at start of ADT with a manageable increase in toxicity. ADT (+/- RT) + abiraterone is a new standard of care for this group. Clinical trial information: NCT00268476

CARE Faculty Perspective:

Abiraterone has established a survival benefit for patients with advanced prostate cancer. The combination of abiraterone, prednisone, and androgen deprivation therapy (ADT) is able to stop the production of hormones directly at the testicular level and through inhibition of CYP17, an enzyme that convers cholesterol in androgens.

The STAMPEDE and LATITUDE trials support the use of upfront treatment of abiraterone with prednisone and ADT for advanced prostate cancer. The STAMPEDE trial investigated almost 2000 patients.  Patients were eligible if they had metastatic disease, or if they had local/locoregional disease with high risk features.  For all comers, the 3-year survival rate when adding abiraterone and prednisone to ADT was 83% compared to 76% when using ADT alone. The LATITUDE trial concluded that when abiraterone (with prednisone) is added to ADT therapy, a 38% improvement in OS was noted and PFS was 33 months compared with 14.8 months with ADT alone. These results could change the treatment paradigm of patients with advanced but castrate sensitive disease moving forward.

There is still much to be learned about the optimal treatment combination or sequence. We still do not know how abiraterone compares to docetaxel, and whether combination of the two is better than either agent alone. It will be interesting to see the results of trials looking at these types of combinations that are currently underway, such as the PEACE 1 & 2 trials and the ENZAMET study (although patients were randomized to enzalutamide or bicalutamide, roughly 50% of patients in either arms also received docetaxel as part of standard of care). This will give us an idea of the impact of abiraterone and docetaxel with ADT, and how the standard-of-care may be impacted.

Whether abiraterone is better than docetaxel, at least in patients with metastatic disease, remains untested in head to head randomized trials.  However, as eloquently shown by Eric Small during his discussion of the two studies, the results observed in LATITUDE seem to quite closely mirror the results of CHAARTED – given the cost and toxicity differences in these two treatment approaches, deciding on an optimal regimen in these patients may require a personalized approach and payers may potentially end up taking some the decisions away from the prescriber and patient. 

Treatment efforts do not end with this combination. It is also important to consider treatment sequencing after a patient [inevitably] progresses. Recent retrospective trials focused on sequencing have suggested that post- ADT, chemotherapeutic options (docetaxel followed by cabazitaxel) may extend OS. It is therefore important to monitor patients closely with PSA and regular imaging and not wait until symptomatic progression to consider further treatment. Otherwise, the opportunity to maximize subsequent lines of therapy may be less effective and/or not valid.

With the number of specialists involved in the management of prostate cancer (i.e. medical oncologists, urologists, radiation oncologists), collaboration and education on the entire course of therapy is of value, along with considerations for referral to another specialist if the patient’s current management approach is no longer working.

 

Press Release: CARE Congress on Biosimilars

On January 13th, 2017 CARE faculty specialists representing the fields of gastroenterology, hematology, oncology, respirology and rheumatology met to consider the integration of Biosimilars into the Canadian healthcare system.

Biosimilars are drugs that may replace expensive biologic drugs that are going off patent.  With biosimilars being relatively new to the Canadian landscape, there are also a number of questions/considerations on extrapolating data, interchangeability, immunogenicity, and systemic challenges (tracking and monitoring) that require attention.

Recognizing both the potential impact on the Canadian healthcare system and the importance of involving stakeholders, CARE faculty invited 16 speakers representing Canadian researchers, clinicians, Health Canada, public and private funding agencies, health economists, hospital pharmacists, nurses, advocacy groups, ethicists and legal experts to share perspectives, concerns, wants and needs.

An audience of 100+, representing the above named stakeholders, along with various levels of government, pharmaceutical companies and industry associations, listened in while speakers and assembled faculty discussed biosimilars from multiple perspectives.

The aim of this Congress is to increase collective understanding, consider education needs for specialists and assembled stakeholders, and ultimately refine a CARE guidance/position on Biosimilars.

 

CARE Faculty believes: 

  • Developing clinical practice through optimization of current therapies
  • Improving patient outcomes by developing innovative therapeutics
  • Ensuring access to quality care for all Canadians by the responsible and evidence-based use of treatment
  • Competition is welcomed to improve efficiency and access

 

CARE™ funding sources:

CARE™ receives unrestricted funding from multi-industry sponsors, institutions and associations. Content reflects the opinions, presentations and analyses of experts, investigators, educators and clinicians ("CARE Faculty"), whose activities, while independent, are commercially supported by the noted sponsor(s). Program content is developed independently of sponsor(s).

 

Background Steps that led up to this CARE™ Congress

  • CARE™ conducted needs assessments in oncology, hematology, rheumatology, and gastroenterology to understand current perceptions of biosimilars and their use in Canada
  • A multi-disciplinary group of CARE faculty members met October 27th, 2016 to discuss the various needs assessment data, and the impact biosimilars will have in Canada
  • There was consensus to host a larger meeting involving more stakeholders; CARE™ has worked to quickly assemble this Congress involving not only different specialties, but different stakeholder representatives.

For more information on the steering faculty, assembled CARE faculty, speaker list, or for questions/information needs regarding CARE, please contact Christina Lopes or Erica Duncan. 

 


References:

  1. Hirsch BR, Lyman GH. Biosimilars: are they ready for primetime in the United States? J Natl Compr Canc Netw. 2011;9: 934–943
  2. Based on 2013 sales of biologics with patents expiring before 2021 (Remicade, Eprex, Aranesp, Levemir, Humira, Avastin, Enbrel, Lucentis, Rituxan, Gonal-F). IMS Health Canada - Canadian Drug and Hospital (CDH) Sales, December 2013, page 11

Click here to view more highlights from the CARE Congress on Biosimilars.

Insights on the NOR-SWITCH trial are now available! Hear from Canadian experts Drs. Brian Feagan & John Marshall

Biologic therapy has revolutionized the treatment of IBD and improved patient outcomes drastically. Many of the biologic therapies we routinely use are now or soon going off patent and competitive molecules, subsequent entry biologics (SEBs), are now being introduced. SEBs have potential implications for our own practices but also for how we manage our pharmacy budgets and how we deliver health care in Canada.

The NOR-SWITCH trial was a randomized, open-label trial studying a cohort of patients who were stable or in remission on the innovator biologic, infliximab (REMICADE®). Patients were randomized to either continue with infliximab or switch to a SEB version of infliximab (INFLECTRA® in Canada). This was a cross specialty trial that included patients from a variety of diagnoses, including: rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, UC, CD and chronic plaque psoriasis. Each group was followed for different endpoints over the course of the trial.

CARE Gastroenterology Faculty lead, John Marshall (McMaster University), sat down with Dr. Brian Feagan (Professor of Medicine at the University of Western) to critically assess this study and discuss how the results should be interpreted and applied in Canadian practice.

 

Interested in learning more? Join us at The CARE Congress on Biosimilars!

ESMO 2016 News in Oncology: Genitourinary Cancer

ESMO 2016. Abstract 819P. Real world outcomes of patients with metastatic renal cell carcinoma (mRCC) using first-line sunitinib or pazopanib: The Canadian experience

A. Lalani et al.

Results: Our cohort included 670 patients: 93 treated with pazopanib and 577 with sunitinib. Median TTF was greater in patients treated with sunitinib versus pazopanib (6.0 vs 3.7 mos, p = 0.046) and maintained significance when adjusted for IMDC criteria (hazard ratio [HR] 0.61, 0.41-0.90 95% CI, p = 0.013). Median OS was better in patients treated with sunitinb (31.9 vs 20.6 mos, p = 0.028) and maintained significance when adjusted for IMDC criteria (HR 0.60, 0.38-0.95 95% CI, p = 0.028). Common toxicities requiring dose modification, including fatigue and diarrhea, were similar between both groups. However, patients treated with sunitinib had a significantly higher incidence of mucositis, hand-foot syndrome, and GERD; patients treated with pazopanib had a significantly higher incidence of liver toxicity and a trend towards weight loss.

Conclusions: In Canadian patients with clear cell mRCC, survival and treatment duration appears to favour sunitinib over pazopanib. Plausible explanations include potential differences in patient selection for pazopanib, the contemporary experience with individualized dosing on sunitinib, and small sample size. These data on real world toxicities are informative and may aid physicians and patients in guiding treatment decisions.

CARE Faculty Perspective: The results of this study should be interpreted within the limitations of a real-world data set, including the retrospective data collection and potential selection bias. Real world outcomes for sunitinib and pazopanib compare favourably to the outcomes observed in phase III studies.

Overall survival in this Canadian patient population was superior for patients treated with sunitinib vs pazopanib, even when adjusted for IMDC prognostic factors. Whether this result is due to bias or patient selection or other factors such as the use of dose/schedule individualization for sunitinib should be further examined. The results of the Canadian prospective study on sunitinib dose/schedule individualization are eagerly awaited.

 


 

ESMO 2016. 738P. Meta-analysis of randomized clinical trials in metastatic castration resistant prostate cancer: Comparison of hypertension, neurological and psychiatric adverse events on enzalutamide and abiraterone acetate plus prednisone treatment

P. Ruiz Gracia et al.

Results: RR for hypertension (all grades) was 2.26 (1.06-4.81) for ENZ and 1.61 (1.30-2.00) for AA + P, for hypertension grade 3 was 2.52 (1.61-3.95) and 1.72 (0.97-3.06) respectively. The RR for neurological disorders was 1.44 (1.31-1.58) for ENZ and 1.13 (0.99-1.29) for AA + P. RR for psychiatric disorders was 1.43 (1.21-1.69) for ENZ and 1.04 (0.9-1.20) for AA + P. No evidence of publication bias was observed.

Conclusions: The aim of this study is to contrast the hypertension, psychiatric and central nervous system disorders safety profile of AA + P and ENZ. This analysis suggests that mCRPC patients treated with ENZ had a higher risk of developing hypertension, neurological and psychiatric disorders than the patients treated with AA + P. One may speculate that the affinity of ENZ for GABA receptor may play a role in the toxicities related to the central nervous system.

CARE Faculty Perspective:

Selecting a therapy for patients with mCRPC is challenging, and there are many factors to consider, including safety (ie. adverse events/toxicities) and efficacy.

This meta-analysis found a higher level of toxicities related to the CNS (neurological & psychiatric disorders) as well as hypertension with enzalutamide vs. abiraterone

 Based on a patient’s individual fitness level, age, comorbidities, etc., this slight increase in toxicities is something to consider when choosing a therapy for a patient with mCRPC. 

ASCO 2016: News in Prostate Cancer - Abstract 5059

News in Prostate Cancer

ASCO 2016. Abstract 5059. Effects of abiraterone (ABI) and enzalutamide (ENZA) on cognitive impairment and depressive symptoms in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Sunil Parimi et al.

Results: 60 pts with a minimum follow-up of 3 months were evaluated: 27 and 33 were randomized to ABI and ENZA,
respectively. 10 were non-evaluable for Montreal Cognitive Association (MoCA) test and 7 for Patient Health Questionnaire (PHQ-9) data. At baseline, median score for MoCA was 25 (range 13-30) and 3 for PHQ-9 (range 0-20). Similar proportions of pts in the ABI and ENZA arms had some baseline impairment in PHQ9 (33.3%, 31.3%) and MoCA scores (76.9%, 74.2%). Change from baseline to Cycle 4 in MoCA and PHQ-9 severity levels are shown in the Table. There was a trend for a greater proportion of pts treated with ENZA as compared to ABI to have a worsening cognitive impairment score (p = 0.20). Significantly more pts in the ENZA arm had a worsening depression severity score (P = 0.03). A greater number of ENZA pts reported worsening on PHQ-9 questions related to energy, appetite, and psychomotor symptoms. 

Conclusions: In this preliminary analysis, there were more pts with a worsening severity of reported depression symptoms and a trend towards an increase in cognitive impairment with ENZA as compared to ABI. These data help to characterize and define the incidence of these symptoms. Clinical trial information: NCT02125357

 CARE Faculty Perspective: This study was conducted in Canada and was one of the first head-to-head trials of abiraterone and enzalutamide that compared cognitive impairment and depressive symptoms in patients with metastatic castrate resistant prostate cancer.

With the variety of available agents in this category, we must consider a number of factors to determine which agent to use first,  and which sequence of agents is optimal for a given patient. One of the most important of these factors is toxicity, as side effects of therapy can have a negative impact on patients’ quality of life and their compliance to treatment. From the very preliminary, short term results of this study, it appears that patients who received abiraterone may have had an improvement in overall patient health/depressive symptoms (ie. increased energy, appetite, etc.) and cognitive impairment, compared to enzalutamide.

 While this is an interesting study to consider, data is still early and the sample size was modest.We await further data to verify these findings.