SUMMARY: Prostate cancer is the most common cancer in American men excluding skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 men will die of the disease. The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence.
The American Urological Association suggested that a PSA of 0.2 ng/mL or higher after Radical Prostatectomy, defines PSA failure or relapse. A PSA rise of 2 ng/ml or more above post Radiation Therapy nadir is considered PSA failure or relapse. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. The appropriate time (immediate versus delayed) to start Androgen Deprivation Therapy (ADT) in patients with prostate cancer with rising Prostate-Specific Antigen (PSA), as the only sign of relapse, has remained unclear. This has been partly due to lack of patient accruals and patient reluctance to be randomized, in these clinical trials.
The authors conducted this randomized, prospective, phase III trial, to determine if immediate intervention with Androgen Deprivation Therapy (ADT) would improve Overall Survival (OS), compared with delayed ADT, in prostate cancer patients with PSA relapse, following definitive therapy, or in asymptomatic men not suitable for definitive therapy at the time of diagnosis. This analysis combined prostate cancer patients with PSA relapse enrolled in two separate studies. Two hundred and ninety three (N=293) eligible patients were randomly assigned 1:1 to immediate Androgen Deprivation Therapy (N= 142) or delayed ADT (N=151). The primary endpoint was unadjusted Overall Survival. Secondary endpoints included cancer-specific survival and time to clinical progression. The median follow up was 5 years. There was a statistically significant improvement in the Overall Survival, with a 45% reduction in the risk for death, for those receiving immediate ADT compared with the delayed treatment group (HR=0.55; P=0.05). Further, with immediate ADT, there was a statistically significant delay in the time to first local progression (HR= 0.51; P=0.001) as well as time to first metastatic disease (HR=0.54; P=0.018). The authors concluded that immediate Androgen Deprivation Therapy significantly improved Overall Survival and time to clinical progression for prostate cancer patients with PSA relapse, after definitive therapy. This benefit however must be weighed against the risks associated with long term Androgen Deprivation Therapy. TROG 03.06 and VCOG PR 01-03: The “Timing Of Androgen Deprivation therapy in prostate cancer patients with a rising PSA (TOAD)” collaborative randomised phase III trial. Duchesne GM, Bassett J, D’Este C, et al. J Clin Oncol 33, 2015 (suppl; abstr 5007)
It is postulated that Aspirin also works by COX-independent mechanisms such as, the inhibition of NF-kB and Wnt/ β-catenin signaling, which may play a role in its chemopreventive properties. Even though the benefits of Aspirin in the primary prevention of CRC remains well established, the role of Aspirin in secondary prevention in patients with CRC is unclear. The authors conducted this trial to evaluate the association between Aspirin use after diagnosis of CRC with CRC-Specific Survival (CSS) and Overall Survival (OS) in the largest group of patients ever studied. The study authors in this retrospective study identified 25,644 patients in the Cancer Registry of Norway, diagnosed with ColoRectal Cancer (CRC) from 2004 through 2011. Using the Norwegian Prescription Database, the authors were then able to establish that 6,109 patients in this large cohort had documented exposure to Aspirin. Exposure to Aspirin was defined as a prescription for more than 6 months of Aspirin following a diagnosis of CRC. The median follow up was 2.2 years. The authors performed a multivariate regression analysis controlling for age, gender, tumor stage, tumor differentiation and noted that exposure to Aspirin post-diagnosis, independently improved ColoRectal Cancer (CRC) -Specific Survival (HR=0.75; P<0.001) and Overall Survival (HR=0.86; P<0.001). The authors concluded that in this large group of unselected ColoRectal Cancer (CRC) patients, exposure to Aspirin after the diagnosis of CRC is independently associated with improved Colorectal Cancer-Specific Survival and Overall Survival. They added that because of the risk of bleeding, the risk–benefit should be assessed before Aspirin is routinely recommended to this patient population. Impact of aspirin as secondary prevention in an unselected cohort of 25,644 patients with colorectal cancer: A population-based study. Bains S, Mahic M, Cvancarova M, et al. J Clin Oncol 33, 2015 (suppl; abstr 3504)
Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, PD-1(Programmed cell Death-1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. The first Immune checkpoint protein to be clinically targeted was CTLA-4. YERVOY® (Ipilimumab) , an antibody that blocks Immune checkpoint protein/receptor CTLA- 4, has been shown to prolong overall survival in patients with previously treated, unresectable or metastatic melanoma. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. The U. S. Food and Drug Administration granted approval to OPDIVO®, for the treatment of patients with metastatic Squamous Non-Small Cell Lung Cancer (NSCLC), with progression on or after platinum based chemotherapy. CheckMate 057 is a randomized, international, phase 3 study designed to evaluate the benefit of OPDIVO® for patients with Non-Squamous (NSQ) NSCLC who had progressed after platinum-based doublet chemotherapy. A total of 582 patients were randomized to receive OPDIVO® 3 mg/kg IV every 2 weeks (n=292) or TAXOTERE® 75 mg/m2 IV every 3 weeks (n=290). Eligible patients included those with advanced Non-Squamous NSCLC who had progressed after platinum-based doublet chemotherapy and a Tyrosine Kinase Inhibitor (TKI), if deemed eligible for a TKI. Treatment was continued until disease progression or unacceptable toxicity. The primary clinical endpoint was Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR), Progression Free Survival (PFS), Efficacy based on PD-L1 expression, Quality of Life, and Safety. The study was stopped earlier than expected following assessment by the independent Data Monitoring Committee (DMC) which concluded that the study met its endpoint, demonstrating superior overall survival, in patients receiving OPDIVO®, compared to the control group. Patients in the OPDIVO®, group had a significantly higher median OS compared to those in the TAXOTERE® group (12.2 months versus 9.4 months, Hazard Ratio [HR] 0.73, P=0.0015). This meant a 27% reduction in the risk of death in the OPDIVO® group and this survival benefit was seen in all predefined subgroup of patients. The Objective Response Rate (ORR) was also significantly higher for patients receiving OPDIVO® compared to TAXOTERE® (19% versus 12%, P=0.0246) and the median duration of response (DOR) was significantly higher for the OPDIVO® group (17.2 months) vs the TAXOTERE® group (5.6 months). More importantly, when tumor PD-L1 expression was correlated with Overall Survival, the median OS for OPDIVO® was 17.2 months, 18.2 months, and 19.4 months for patients with tumors having 1% or higher, 5% or higher, and 10% or higher of cells staining positive for PD-L1, respectively, compared with 9.0 months, 8.1 months, and 8.0 months with TAXOTERE® treatment. Even though this study showed significant survival outcomes for patients expressing any level of PD-L1, the magnitude of benefit was even more so, in patients with tumors expressing higher levels of PD-L1. PD-L1 expression may therefore be a predictor of response, although this should not yet be used for patient selection. Grade 3-5 adverse events occurred more often in the TAXOTERE® group compared to the OPDIVO® group (54% vs 10%). Based on this compelling data, the authors concluded that OPDIVO® significantly improves Overall Survival when compared to TAXOTERE®, in patients with advanced non-Squamous NSCLC, after failure of platinum based doublet therapy. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). Paz-Ares L, Horn L, Borghaei H, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA109)</s
By virtue of its dual mechanism of action, it targets and destroys Myeloma cells and also enhances the activation of Natural Killer cells. Previously published phase Ib/II study, has shown encouraging activity, when Elotuzumab was combined with REVLIMID® and Dexamethasone, in patients with Relapsed/Refractory Multiple Myeloma (RRMM). ELOQUENT-2 is an open-label phase III trial in which 646 patients with Relapsed/Refractory Multiple Myeloma were randomized in a 1:1 ratio to receive Elotuzumab in combination with REVLIMID® and Dexamethasone (N=321) or REVLIMID® and Dexamethasone alone (N=325). Enrolled patients had 1–3 prior therapies and were not REVLIMID® refractory. Prior therapies included VELCADE® (Bortezomib), THALOMID® (Thalidomide) and REVLIMID®. Approximately 35% of the enrollees were refractory to the last therapy, 32% had del(17p) and 9% had t(4;14). The median age was 66 years. Elotuzumab was administered at 10 mg/kg IV weekly for the first two cycles and then once every 2 weeks thereafter. REVLIMID® was given at 25 mg orally on days 1 thru 21 of each cycle along with Dexamethasone 40 mg weekly. In the Elotuzumab group, Dexamethasone was dosed at 28 mg orally plus 8 mg IV on the weeks when Elotuzumab was administered. The cycle duration was 28 days. Treatment was administered until disease progression or unacceptable toxicity. Primary endpoints were Progression Free Survival (PFS) and Overall Response Rate (ORR). At a median follow up of 24 months, PFS in the Elotuzumab group was 19.4 months compared to 14.9 months in the REVLIMID®/Dexamethasone alone group (HR=0.70; P=0.0004). The 1-year PFS for the Elotuzumab versus control group was 68% vs 57% respectively and the 2-year PFS was 41% vs 27%. This benefit was seen across all subgroups including those with unfavorable cytogenetics. The ORR was 79% in the Elotuzumab group and 66% in the control group. (P = 0.0002). At the time of this interim analysis, more patients in the Elotuzumab group remained on therapy (35%) compared to the control group (21%) and treatment discontinuation was mainly for disease progression. Grade 3–4 toxicities occurred in 15% or more patients in the Elotuzumab group and included neutropenia and anemia. The authors concluded that Elotuzumab with its novel immunotherapeutic mechanism of action, when added to REVLIMID® and Dexamethasone, reduced the risk of disease progression by 30% in patients with Relapsed/Refractory MultipleMyeloma, and this was accomplished with manageable toxicities. Patients in this study are being followed up for long term outcomes including Overall Survival. Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;(suppl; abstr 8508).</s
The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. Chemotherapy is usually considered for patients who progress on hormone therapy and TAXOTERE® (Docetaxel) has been shown to improve Overall Survival (OS) of metastatic prostate cancer patients, who had progressed on androgen deprivation therapy. It is not clear however, whether ADT is more effective with or without TAXOTERE®, when treating patients with metastatic prostate cancer. To address this further, a randomized phase III trial (E3805) was conducted to assess the benefit of upfront treatment with a combination of chemotherapy and hormonal therapy, in patients with metastatic hormone sensitive prostate cancer. Seven hundred and ninety (N=790) patients with newly diagnosed metastatic prostate cancer were randomly assigned to receive either Androgen Deprivation Therapy alone (N=393) or ADT plus TAXOTERE® (N=397). Androgen Deprivation Therapy consisted of either Luteinizing Hormone Releasing Hormone (LHRH) agonist therapy, LHRH antagonist therapy, or surgical castration. Chemotherapy consisted of TAXOTERE®, started within 4 months of starting ADT, dosed at 75 mg/m2 given every 3 weeks for a maximum of six cycles. The median age of patients was 63 years and approximately two-thirds of patients had high-volume disease, with either extensive liver or bone metastases. The primary endpoint of this study was Overall Survival. At a median follow up of 29 months, the median Overall Survival was 42.3 months in the ADT group and 52.7 months in the ADT plus TAXOTERE® group (HR=0.63; P<0.0006). This benefit was even more significant in patients with high volume disease (32.2 vs 49.2 months for ADT and ADT plus TAXOTERE® respectively, HR=0.62; P<0.0012). At 12 months, the proportion of patients with PSA levels less than 0.2 ng/mL was 9.4% in the ADT alone group vs 19.7% in the ADT plus TAXOTERE® group (P < 0.0001). The median time to clinical progression was 19.8 months in the ADT alone group vs 32.7 months in the ADT plus TAXOTERE® group (P < 0.0001). The authors concluded that this is the first study to demonstrate survival benefit in patients with newly diagnosed metastatic prostate cancer. This survival benefit with Androgen Deprivation Therapy and TAXOTERE® is even more so, in patients with high volume disease and should be considered standard treatment for those patients who are fit to receive TAXOTERE® based therapy. Sweeney C, Chen Y, Carducci MA, et al. 2014 ASCO Annual Meeting; LBA2
This latest approval was based on the results of an international, randomized, open-label phase III trial in which 487 patients with stage II to IV MCL, who were ineligible or not considered for Bone Marrow Transplantation, received VR-CAP (N = 243) or R-CHOP (N = 244). VR- CAP is essentially R-CHOP with the Vincristine replaced by VELCADE®. So, VR-CAP regimen consisted of VELCADE® administered IV at 1.3 mg/m2 on days 1, 4, 8, and 11, RITUXAN® (Rituximab) 375 mg/m2 IV given on day 1, Cyclophosphamide 750 mg/m2 IV on day 1, Doxorubicin 50 mg/m2 IV on day 1 and Prednisone at 100 mg/m2 PO on days 1 to 5 of a 21 day cycle for 6-8 cycles. R-CHOP regimen was exactly similar except that Vincristine 1.4 mg/m2 (max 2 mg) IV was administered on day 1 of each cycle instead of VELCADE®. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Time To Progression (TTP), Time To Next Treatment (TTNT), Overall Survival (OS) and safety. Patients received a median of 6 cycles and after a median follow up of 40 months, patients in the VR-CAP group demonstrated a significantly longer median PFS (25 months vs. 14 months; HR=0.63;P<0.001) with a 37% relative improvement in the PFS compared to those who were treated with standard R-CHOP. Patients in the VR-CAP group also had a higher overall response rate (88 vs 85%) and a higher rate of complete response (44% vs. 34%). The most common adverse reactions occurring in 20% or more of patients receiving the VR-CAP regimen were neutropenia, leukopenia, anemia, thrombocytopenia, lymphopenia, peripheral neuropathy, pyrexia, nausea and diarrhea. Infections were reported for 31% of patients in the VR-CAP group compared to 23% of the patients in the R-CHOP group. The authors concluded that VR-CAP significantly prolonged PFS and consistently improved secondary efficacy endpoints, compared to R-CHOP, in newly diagnosed, Bone Marrow Transplant ineligible Mantle Cell Lymphoma patients with manageable toxicity. Proteosome inhibition with a VELCADE® based chemotherapy regimen has opened the doors for more effective therapies for Mantle Cell Lymphoma patients. Cavalli F, Rooney B, Pei L, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8500)</s
Acute CINV begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment whereas delayed nausea and vomiting occurs more than 24 hours after chemotherapy administration and can persist for several days. Delayed CINV is often underestimated and a third of the patients receiving chemotherapy may experience delayed nausea and vomiting without prior acute nausea or vomiting. Acute nausea and vomiting is dependent on serotonin (5-hydroxytryptamine-5HT3) and its receptors. 5-HT3 receptors are located on vagal afferent pathway, which in turn activates the vomiting center to initiate the vomiting reflex. 5-HT3 receptors are located peripherally on the nerve endings of the vagus and centrally in the Chemoreceptor Trigger Zone of the area Postrema. Chemotherapeutic agents produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Delayed nausea and vomiting is associated with the activation of Neurokinin 1 (NK1) receptors by substance P. NK1 receptors are broadly distributed in the central and peripheral nervous systems. Netupitant inhibits substance P mediated responses. ALOXI® (Palonosetron) is a second generation 5-HT3 antagonist and has a 100 fold higher binding affinity to 5-HT3 receptor than other 5-HT3 receptor antagonists. AKYNZEO® (300 mg Netupitant/0.5 mg Palonosetron) is an oral, fixed combination product of Netupitant, a substance P/Neurokinin 1 (NK1) receptor antagonist, and ALOXI®, a serotonin (5- HT3) receptor antagonist. 
Taking advantage of the different mechanisms of action and synergy between these two agents, a randomized, double-blind, multinational study was conducted, comparing AKYNZEO® with ALOXI® in chemotherapy naive patients receiving anthracycline based chemotherapy regimens. One thousand four hundred and fifty five (N=1455) were randomized to receive either AKYNZEO® or ALOXI® and both groups received oral Dexamethasone as a part of their antiemetic regimen. The primary endpoint was complete response (CR) defined as no emesis, no rescue medication needed and no significant nausea. AKYNZEO® maintained superiority over ALOXI® for overall (0-120 hours) complete response and also maintained superiority over multiple chemotherapy cycles (P < 0.0001). The most common side effects for AKYNZEO® were headache, fatigue and constipation. The authors concluded that AKYNZEO®, by targeting dual antiemetic pathways, significantly improved chemotherapy induced nausea and vomiting compared to ALOXI® alone and this benefit was maintained over multiple cycles of moderately emetogenic chemotherapy. AKYNZEO® capsule can be administered as a single dose, one hour prior to the start of chemotherapy. Aapro MS, Karthaus M, Schwartzberg LS, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 9502)</s