Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer ASCO Clinical Practice Guideline

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 164,690 new cases of prostate cancer will be diagnosed in 2018 and 29,430 men will die of the disease. Prostate cancer patients with newly diagnosed radiographic evidence of metastatic disease, either as part of a de novo diagnosis of prostate cancer, or as a manifestation of disease progression from an earlier clinical disease state, are considered to have “clinical metastatic: non-castrate” disease, by Prostate Cancer Working Group, provided that they have testosterone levels in the non-castrate level (more than 50 ng/dL). These patients may or may not have received limited courses of Androgen Deprivation Therapy (ADT) for their earlier clinical states.

The standard therapy for newly diagnosed metastatic non-castrate prostate cancer has been ADT alone. Upon progression, these patients are described as having metastatic Castration Resistant Prostate Cancer (mCRPC). These patients are continued on ADT and are offered additional treatments.

The ASCO multidisciplinary Expert Panel developed this guideline, following a systematic review of all phase III randomized controlled trials and meta-analyses, published from 2015 through October 2017. These studies included men with metastatic non-castrate prostate cancer (testosterone levels more than 50 ng/dL), being considered for treatment with Docetaxel (TAXOTERE®) or Abiraterone (ZYTIGA®), in addition to ADT. The Clinical Practice Guidelines are provided by the American Society of Clinical Oncology, (ASCO) to assist providers in clinical decision making.

This clinical practice guideline addresses the addition of Abiraterone or Docetaxel to Androgen-Deprivation Therapy (ADT) for metastatic prostate cancer, that has not been treated (or has been minimally treated) with testosterone-lowering agents.

Guideline Question: Is there an Overall Survival (OS) advantage associated with the addition of Docetaxel or Abiraterone to Androgen-Deprivation Therapy (ADT) in men with metastatic non-castrate prostate cancer? Other outcomes of interest include Progression-Free Survival (PFS), Failure-Free Survival (FFS), PSA response, Overall Response Rate, and Quality of Life (QOL).

Target Population: Men with metastatic non-castrate prostate cancer being considered for treatment with ADT.

Key Recommendations and Qualifying Statements:

ADT Plus Docetaxel

1) Docetaxel in addition to to ADT should be offered for men with metastatic non-castrate prostate cancer with High-Volume Disease (HVD), who are candidates for treatment with chemotherapy, as the strongest evidence of benefit for Docetaxel is for those men who were diagnosed with de novo metastatic disease or HVD, per CHAARTED study.

2) CHAARTED trial is a randomized phase III trial in which patients with newly diagnosed metastatic prostate cancer, were randomly assigned to receive either Androgen Deprivation Therapy alone or ADT plus Docetaxel. The addition of Docetaxel to ADT significantly prolonged Overall Survival in men with High-Volume Disease.

3) In the CHAARTED study, High-Volume Disease was defined as four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or the presence of any visceral disease. The criteria were agnostic to the presence or absence of nodal disease.

4) For patients with Low-Volume Disease (LVD) and who are candidates for chemotherapy, Docetaxel plus ADT may be offered per CHAARTED study. However, the strength of the evidence to support an OS benefit is less compelling for men who do not have de novo metastatic disease and/or who do not meet the HVD criteria. A subset analysis of CHAARTED did not demonstrate a survival benefit for Low-Volume Disease, and the GETUG-15 trial was negative.

5) The appropriate regimen of Docetaxel is 75 mg/m2 every 3 weeks for 6 cycles either alone or with prednisolone.

ADT Plus Abiraterone

1) For men with high-risk, de novo metastatic non-castrate prostate cancer, Abiraterone in addition to ADT should be offered per LATITUDE study.

2) LATITUDE is a randomized, double-blind, placebo-controlled, phase III trial, which evaluated the clinical benefit of adding Abiraterone along with Prednisone to Androgen Deprivation Therapy (ADT), as compared with ADT and placebo, in patients with newly diagnosed, metastatic non-castrate prostate cancer. The addition of Abiraterone to ADT significantly increased Overall Survival and radiographic Progression Free Survival, in this patient group.

3) LATITUDE trial defined high-risk factors associated with a poor prognosis and included at least two of the following three high-risk factors: a Gleason score 8 or greater, 3 or more bone lesions, and presence of measurable visceral disease.

4) For men with lower-risk de novo metastatic non-castrate prostate cancer, Abiraterone may be offered per STAMPEDE study. STAMPEDE trial did not include a high risk definition.

5) LATITUDE and STAMPEDE are mutually supportive for treating high-risk disease with ADT and Abiraterone, with only STAMPEDE furnishing evidence that includes men with lower-risk disease.

6) The appropriate regimen is Abiraterone 1000 mg with either prednisolone or prednisone 5 mg orally once daily, until treatment(s) for mCRPC are initiated.

Docetaxel and Abiraterone

Docetaxel and Abiraterone should be considered as two separate standard treatments for metastatic non-castrate prostate cancer. These two standards have not been compared head to head, and their benefits seem to be quite similar. It is not known which patient subgroups might do better with one standard as opposed to the other and therefore practical factors should be taken into consideration. The use of both standards in combination or in series has not been assessed and therefore cannot be recommended.

In summary, the addition of either Docetaxel or Abiraterone to ADT in men with newly diagnosed metastatic prostate cancer offers a survival benefit, as compared with the use of ADT alone. In the absence of randomized data comparing the addition of Docetaxel versus Abiraterone to ADT in men with metastatic non-castrate disease, additional variables including patient comorbidities, toxicity, QOL considerations, drug availability, and cost will ultimately need to be taken into consideration.

Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Morris MJ, Rumble RB, Basch E, et al. J Clin Oncol 2018;36:1521-1539.

Late Breaking Abstract – ASCO 2018 First Line TECENTRIQ® plus Chemotherapy in Advanced Squamous NSCLC

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas, and 10% are Large cell carcinomas. Non Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, and less than 15% of patients with advanced Squamous NSCLC survive a year after diagnosis and less than 5% of patients survive for five years or longer. Immunotherapy is an accepted second line intervention after Platinum-based chemotherapy, in patients with advanced NSCLC, and is an approved first line therapy, for patients with high PD-L1 expressing tumors (50% or more).

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors and thus enabling the activation of T cells. TECENTRIQ® was approved by the FDA in October 2016 for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose disease progressed during or following Platinum-containing chemotherapy. In this present publication, the authors studied the efficacy of TECENTRIQ® given along with combination chemotherapy, in patients with advanced Squamous NSCLC.Unleashing-T-Cell-Function-with-Anti-PDL1-Antibodies

IMpower131 is a multicenter, open-label, phase III study, in which 1021 chemotherapy-naïve patients with stage IV Squamous NSCLC were randomly assigned in 1:1:1 ratio to receive TECENTRIQ® along with Carboplatin, and Paclitaxel (Group A, N=338), TECENTRIQ® along with Carboplatin, and ABRAXANE® (nab-paclitaxel) (Group B, N=343) and the control arm of Carboplatin and ABRAXANE® (Group C, N=340). Patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and TAXOL® (Paclitaxel) 200 mg/m2 IV, all drugs given on Day 1, every 21 days. Patients in Group B received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 IV on Day 1 and ABRAXANE® 100mg/m2 IV on Days 1, 8, and 15 of each 21-day cycle. Patients in Group C (control group) received Carboplatin AUC 6 IV on Day 1 and ABRAXANE® 100mg/m2 IV on Days 1, 8, and 15 of each 21-day cycle. Patients received 4-6 cycles of this combination treatment and in Groups A and B, TECENTRIQ® alone was continued as long as there was a clinical benefit, without evidence of disease progression. Tumors were tested for PD-L1 expression, but patients were included in the study regardless of PD-L1 expression level. Patients with tumors demonstrating EGFR or ALK gene changes should have received molecularly targeted treatments before enrolling in this study. The co-Primary endpoints for this study were Progression Free Survival (PFS) and Overall Survival (OS). As per the study design, the current analysis compared the outcomes of patients in Group B with Group C. Outcomes data comparing Group A with Group C are not yet available.

At the time of primary analysis, with a median follow up of 17.1 months, the median PFS across all PD-L1 subgroups was 6.3 months with the addition of TECENTRIQ® to chemotherapy (Group B) versus 5.6 months in Group C, with chemotherapy alone (HR=0.71; P=0.0001). This represented a 29% reduction in the risk of disease progression or death, with the addition of TECENTRIQ® to chemotherapy. The 12-month PFS rates in Groups B and C were 24.7% versus 12.0%, respectively, suggesting a doubling of PFS benefit with the addition of TECENTRIQ® to chemotherapy. The PFS benefit was more pronounced in those with higher tumor PD-L1 expression. Overall Survival data are not yet mature. The most common side effects with the addition of TECENTRIQ® to chemotherapy included skin rash, colitis, and hypothyroidism.

The authors concluded that this is the first phase III trial of an immunotherapy-based treatment regimen, to demonstrate a significant improvement in Progression Free Survival, in advanced Squamous NSCLC. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. Jotte RM, Cappuzzo F, Vynnychenko I, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA9000)

REVLIMID® plus RITUXAN®, A Potential Chemo-Free Frontline Therapy for Follicular Lymphoma

SUMMARY: The American Cancer Society estimates that in 2018, about 74,680 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,910 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).

Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab).

REVLIMID® (Lenalidomide) is an oral immunomodulatory agent (IMiD) with activity in lymphoid malignancies, primarily through immune modulation (repair T-cell immune synapse dysfunction and Natural Killer cell/T-cell effector augmentation). It additionally has antiproliferative effects. Chemo-free combination immunotherapy with REVLIMID® and RITUXAN® or the R2 regimen, has shown promising activity in phase II studies.GELF-Criteria-for-Initiating-Treatment-of-Follicular-Lymphoma

RELEVANCE is a global, randomized, open-label, phase III study, conducted in partnership with the Lymphoma Academic Research Organisation (LYSARC). This study evaluated the investigational regimen of REVLIMID® plus RITUXAN® (R2), followed by RITUXAN® maintenance, compared to the standard of care treatment of RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance, in patients with previously untreated Follicular Lymphoma.

In this study, 1030 patients with treatment naïve, advanced Follicular Lymphoma, were randomized to R2 regimen (N=513) and R-Chemo regimen (N=517). Patients had Grade 1-3a Follicular Lymphoma, requiring therapy according to GELF criteria. Patients in the R2 group received REVLIMID® 20 mg orally daily on Days 2 thru 22 every 28 days for 6-12 cycles and continued responders received REVLIMID® 10 mg orally daily on Days 2 thru 22 every 28 days, for a total of 18 cycles. RITUXAN® was administered at 375 mg/m2 IV on Days 1, 8, 15, and 22 of cycle 1 and Day 1 of cycles 2 thru 6, and then continued in responders for 12 additional cycles every 8 weeks. R-Chemo group received investigators choice of standard R-CHOP (72%), R-Bendamustine (23%) or R-CVP (5%), and responding patients continued with RITUXAN® 375 mg/m2 IV every 8 weeks, for 12 cycles. The median age of the patients was 59 years. The co-Primary endpoints were Complete Response/unconfirmed Complete Response at 120 weeks and Progression Free Survival (PFS) during the preplanned analysis.

At a median follow up of 37.9 months, PFS was similar in both treatment groups and the 3-year PFS rate was 77% in the R2 group compared with 78% for the R-Chemo group (HR=1.10; P=0.48). The Complete Response/unconfirmed Complete Response at 120 weeks were 48% in the R2 group and 53% in the R-chemo group and this was also not statistically significant (P=0.13). Preliminary Overall Survival outcomes (Secondary endpoint) showed a 3-year survival rate of 94% in both treatment groups. Adverse events were different in the two treatment groups, with a higher incidence of neutropenia and febrile neutropenia in the R-Chemo group, and higher incidence of cutaneous events in the R2 group.

It was concluded that in this first randomized phase III comparison of a chemo-free regimen (R2) with standard R-Chemo, in previously untreated Follicular Lymphoma, a combination of REVLIMID® and RITUXAN® (R2) showed similar efficacy, with a more favorable safety profile, making it a potential chemo-free, firstline option, for patients with Follicular Lymphoma. RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. Fowler NH, Morschhauser F, Feugier P, et al. J Clin Oncol 36, 2018 (suppl; abstr 7500)