Category: Hem/Onc Updates

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

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SUMMARY: Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC were diagnosed in the United States in 2023 and about 52,550 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). These therapies however have shown limited efficacy.

The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis. Currently, no targeted therapies driven by a positive-selection biomarker are approved specifically for the treatment of patients with KRAS-mutated colorectal cancer.

Sotorasib (LUMAKRAS®) is a small molecule that specifically and irreversibly inhibits KRAS G12C protein and traps KRAS G12C in the inactive GDP-bound state, thus blocking downstream proliferation and survival signaling. Unlike the efficacy of single-agent KRAS G12C inhibitors in Non Small Cell Lung Cancer with KRAS G12C mutation, KRAS G12C inhibition alone has limited activity in patients with colorectal cancer. This has been attributed to upstream reactivation of the Epidermal Growth Factor Receptor (EGFR) pathway resulting in treatment-induced resistance, following selective inhibition of KRAS G12C. However, dual KRAS G12C and EGFR blockade can overcome treatment resistance in patients with colorectal cancer with KRAS G12C mutation. In the CodeBreaK 101 Phase 1b trial involving patients with chemorefractory colorectal cancer with mutated KRAS G12C, the Response Rate was 30% with Sotorasib plus Panitumumab, as compared with 9.7% with Sotorasib monotherapy.

CodeBreaK 300 trial is an international, multicenter, open-label, randomized, active-controlled Phase III study, conducted to evaluate the efficacy and safety of two different doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab as compared with the investigator’s choice of standard-care therapy (Trifluridine-Tipiracil or Regorafenib) in patients with chemorefractory metastatic colorectal cancer with KRAS G12C mutation. A lower dose of Sotorasib 240 mg orally once daily was tested in this study because of the nonlinear pharmacokinetic properties of Sotorasib. A total of 160 patients were randomly assigned in a 1:1:1 ratio to receive Sotorasib 960 mg orally once daily plus Panitumumab 6 mg/kg IV every 2 weeks (the 960 mg Sotorasib/Panitumumab group; N=53), Sotorasib 240 mg orally once daily plus Panitumumab (the 240 mg Sotorasib/Panitumumab group; N=53), with each treatment cycle repeating every 28 days, or the investigator’s choice of standard of care therapy which could be either Trifluridine-Tipiracil 35 mg/m2 (up to a maximum of 80 mg per dose) orally twice daily on days 1-5 and days 8-12 every 28 days, or Regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle (N=54). Treatment continued until disease progression or unacceptable toxicities. The median age was 61 years and majority of patients had more than 2 or more lines of previous anti-cancer therapy. KRAS G12C mutation was confirmed by prospective central molecular testing. Randomization was stratified according to previous use of antiangiogenic therapy, the time from initial diagnosis of metastatic disease to randomization and ECOG-PS. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Key Secondary end points included Overall Survival (OS) and Objective Response Rate (ORR).

After a median follow up of 7.8 months, both Sotorasib combinations (960 mg and 240 mg) plus Panitumumab demonstrated significantly longer PFS compared to standard of care therapy. The median PFS was 5.6 months and 3.9 months in the 960 mg Sotorasib/Panitumumab and 240 mg Sotorasib/Panitumumab groups, respectively, as compared with 2.2 months in the standard of care group (HR for 960 mg group=0 49; P=0.006) (HR for 240 mg group=0.58; P=0.03). The improvement in PFS was observed across key subgroups, including tumor sideness/primary tumor location, prior lines of therapy, and the presence or absence of liver metastases. The Objective Response Rate was 26.4%, 5.7%, and 0% in the 960 mg Sotorasib/Panitumumab, 240 mg Sotorasib/Panitumumab, and standard of care groups, respectively. Overall survival data is immature. While this trial was not powered to compare the two Sotorasib/Panitumumab groups directly, the 960-mg dose appeared to yield more clinically significant benefits than the 240-mg dose, across all efficacy endpoints, without additional toxic effects. Grade 3 or higher treatment-related adverse events occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with Sotorasib/Panitumumab.

It was concluded from this study that both doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab resulted in significantly longer Progression Free Survival and a higher incidence of Response Rate than standard treatment. Ongoing analysis and longer follow up will provide additional insights into Overall Survival outcomes.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. Fakih MG, Salvatore L, Esaki T, et al. N Engl J Med 2023;389:2125-2139.

FDA Approves Two Gene Therapies to Treat Patients with Sickle Cell Disease

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SUMMARY: The FDA on December 8, 2023, approved CASGEVY® and LYFGENIA®, representing the first cell-based gene therapies for the treatment of Sickle Cell Disease in patients 12 years and older. Both products are made from the patients’ own hematopoietic stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a Hematopoietic Stem Cell Transplant. Prior to treatment, a patients’ own stem cells are collected, and then the patient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells.

Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder caused by mutations in the hemoglobin beta-globin gene, and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the US is approximately 40-60 years.

HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (Vaso-Occlusive Crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 Thalassemia (double heterozygote for HbS and b-0 Thalassemia) is clinically indistinguishable from HbSS disease. Management of Sickle Cell Disease includes pain control, transfusion support and Hydroxyurea. None of the presently available therapies addresses the underlying cause of this disease nor do they fully ameliorate disease manifestations. Allogeneic bone marrow transplantation can cure this genetic disorder, but less than 20% of eligible patients have a related HLA-matched donor. There is therefore a great unmet need to find new therapies for Sickle Cell Disease.

CASGEVY&reg: (Exagamglogene Autotemcel)
Fetal hemoglobin which consists of two alpha and two gamma chains is produced in utero, but the level of gamma-globulin decreases postnatally as the production of beta-globin and adult hemoglobin, which consists of two alpha and two beta chains, increases. It has been noted that elevated levels of fetal hemoglobin facilitates oxygen delivery, prevents the sickling of red blood cells, and is associated with decreased morbidity and mortality in patients with Sickle Cell Disease. BCL11A gene is a repressor of gamma-globin expression and fetal hemoglobin production in adult red blood cells. Downregulating BCL11A can therefore reactivate gamma-globin expression and increase fetal hemoglobin in RBC.

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nuclease gene editing technique can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. The modified hematopoietic stem cells are transplanted back into the patient where they engraft within the bone marrow and increase the production of fetal hemoglobin. The researchers in this study used this gene-editing technique in Hematopoietic Stem and Progenitor Cells at the erythroid-specific enhancer region of BCL11A to down-regulate BCL11A expression in erythroid-lineage cells, restore gamma-globin synthesis, and reactivate production of fetal hemoglobin. CASGEVY® is the first FDA-approved treatment to utilize CRISPR/Cas9, a type of genome editing technology, to modify patients hematopoietic stem cells.

The FDA approval of CASGEVY® is based on the ongoing single-arm, multi-center trial, involving adult and adolescent patients with Sickle Cell Disease. The trial focused on individuals with a history of at least two protocol-defined severe Vaso-Occlusive Crises (VOCs) during each of the two years prior to screening. The Primary efficacy outcome was freedom from severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period. Out of the 44 patients treated with CASGEVY®, 31 had sufficient follow-up time to be evaluable. Remarkably, 29 of these patients, representing 93.5%, achieved the Primary efficacy outcome, which is freedom from severe VOC episodes for at least 12 consecutive months. Notably, all treated patients achieved successful engraftment, a crucial aspect confirming the efficacy of the CRISPR/Cas9 genome editing technology in modifying hematopoietic stem cells. Importantly, no instances of graft failure or rejection were reported, affirming the safety and viability of CASGEVY® as a therapeutic option. This high success rate underscores the therapeutic potential of CASGEVY® in mitigating the recurrent and debilitating crises associated with Sickle Cell Disease. The most common side effects were stomatitis, cytopenias, febrile neutropenia, nausea, vomiting, headache and itching.

LYFGENIA® (Lovotibeglogene Autotemcel)
LYFGENIA® is a cell-based gene therapy that uses a lentiviral vector as the gene delivery vehicle to add a functional gene to the hematopoietic stem cells, thereby enabling production of HbAT87Q, which is a gene therapy-derived hemoglobin, that functions similarly to hemoglobin A (normal adult hemoglobin produced in persons not affected by Sickle Cell Disease). Red blood cells containing HbAT87Q have a lower risk of sickling , resulting in VOCs. These modified stem cells are then delivered to the patient.

The safety and effectiveness of LYFGENIA® was based on the analysis of data from a single-arm, 24-month, multicenter study in patients with Sickle Cell Disease and history of Vaso Occlusive Events (VOEs). The assessment of efficacy was based on the complete resolution of VOEs between 6 and 18 months after LYFGENIA® infusion. Of the 32 patients included in the study, 88% (28 patients) achieved complete resolution of VOEs within the stipulated timeframe. The most common side effects included stomatitis, cytopenias and febrile neutropenia. Hematologic malignancy has occurred in patients treated with LYFGENIA®, and patients receiving this product should have lifelong monitoring for these malignancies.

In conclusion, the two revolutionary cell-based gene therapies with CASGEVY® and LYFGENIA® heralds a transformative era in the management of Sickle Cell Disease (SCD), for individuals aged 12 and above.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease

FDA Approves AUGTYRO® for ROS1-positive Non-Small Cell Lung Cancer

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SUMMARY: The FDA on November 15, 2023, approved AUGTYRO® (Repotrectinib) for locally advanced or metastatic ROS1-positive Non-Small Cell Lung Cancer (NSCLC). This is the first FDA approval that includes patients with ROS1-positive NSCLC who have previously received a ROS1 Tyrosine Kinase Inhibitor (TKI), in addition to patients who are TKI naïve.

Approximately 1-2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small Cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years) who are relatively young (average age of 50 years), and thus share similar characteristics with ALK-positive patients. ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing. There are currently two FDA-approved treatment options for ROS1-positive metastatic NSCLC- Crizotinib and Entrectinib.

Repotrectinib is a next-generation TKI targeting ROS1 or NTRK-positive locally advanced or metastatic solid tumors, including NSCLC. Repotrectinib was designed to improve durability of response and with favorable properties to enhance intracranial activity.

The FDA approval was based on the results of the TRIDENT-1 global, multicenter, single-arm, Phase I/II, open-label, multi-cohort clinical trial, designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of Repotrectinib, in patients with advanced solid tumors, including locally advanced or metastatic NSCLC. Phase I component of the trial evaluated the safety and pharmacokinetics, whereas in the Phase II component of the study included six distinct expansion cohorts, including TKI-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors. Eligibility requirements included locally advanced or metastatic solid tumors harboring ROS1 or NTRK1-3 gene fusions. Patients with asymptomatic CNS metastases were allowed. Patients received Repotrectinib 160 mg once daily, orally for 14 days, followed by 160 mg twice daily until disease progression or unacceptable toxicities. The Primary endpoint was Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR), and Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and Clinical Benefit Rate (CBR). The efficacy was evaluated in ROS1 TKI-naïve patients (N=71) who received up to one prior line of platinum-based chemotherapy and/or immunotherapy, and in patients who received one prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy (N=56).

In TKI-naïve patients with median follow-up of 24.0 months, the confirmed Objective Response Rate by BICR was 79%, median Duration of Response was 34.1 months and PFS was 35.7 months. In patients with measurable brain metastases at baseline (N=9), intracranial ORR per BICR was 89% and these responses were prolonged.

In patients who received one prior ROS1 TKI with no prior chemotherapy or immunotherapy, at a median follow-up of 21.5 months, the confirmed Objective Response Rate by BICR was 38%, median Duration of Response was 14.8 months and PFS was 9.0 months. In this subset of patients with measurable brain metastases at baseline (N=13), intracranial ORR per BICR was 38%.

The most common adverse reactions were fatigue, dizziness, dyspnea, dysgeusia, peripheral neuropathy, constipation, ataxia, cognitive disorders, and muscular weakness.

It was concluded that the TRIDENT-1 trial demonstrated the efficacy of Repotrectinib in both, TKI-naïve and previously treated patients, showcasing high response rates and durable outcomes. These data will provide physicians with valuable insights into the clinical benefits with Repotrectinib , paving the way for its potential adoption as a new standard of care, in the treatment of ROS1-positive NSCLC. TRIDENT-1 trial is ongoing to assess long term outcomes and additional endpoints across patient populations with ROS1-positive locally advanced or metastatic NSCLC, and NTRK-positive advanced solid tumors.

Repotrectinib in patients with ROS1 fusion-positive (ROS1+) NSCLC: Update from the pivotal phase 1/2 TRIDENT-1 trial. Cho BC, Camidge DR, Lin JJ, et al. Presented at the IASLC 2023 World Conference on Lung Cancer; September 10-12, 2023; Singapore. Abstract OA03.06.

Late Breaking Abstract – ASH 2023: Daratumumab Combination Superior to VRd in Newly Diagnosed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730new cases will be diagnosed in 2023 and 12,590 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease.

Transplantation-eligible patients with newly diagnosed multiple myeloma are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd) induction therapy followed by Autologous Stem-Cell Transplantation, consolidation therapy with VRd, and maintenance therapy with Lenalidomide. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Daratumumab (DARZALEX®) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. Daratumumab exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, Daratumumab may have a role in immunomodulation by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

PERSEUS trial is an open-label, multicenter, randomized Phase III study, conducted to evaluate the efficacy and safety of subcutaneous Daratumumab combined with VRd induction and consolidation therapy and with Lenalidomide maintenance therapy (D-VRd group), as compared with VRd induction and consolidation therapy and Lenalidomide maintenance therapy alone (VRd group), for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma. The subcutaneous formulation of Daratumumab was chosen as it has been found to be noninferior to intravenous Daratumumab, as it is associated with a lower incidence of infusion-related reactions, can be administered in a single dose for all patients, and has a shorter duration of administration of 3-5 minutes.

In this study, 709 eligible patients were randomly assigned in a 1:1 ratio to receive either subcutaneous Daratumumab combined with VRd induction therapy before transplantation, with VRd consolidation therapy after transplantation, and with Lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and Lenalidomide maintenance therapy alone (VRd group). All patients received VRd in six 28-day cycles (four induction cycles and two consolidation cycles) and VRd consisted of Bortezomib 1.3 mg/m2 subcutaneous on days 1, 4, 8, and 11 of each cycle, Lenalidomide 25 mg orally on days 1 through 21 of each cycle, and Dexamethasone 40 mg oral or IV given on days 1-4 and days 9-12 of each cycle. Patients in the D-VRd group also received Daratumumab 1800 mg given subcutaneous weekly during cycles 1 and 2, 1800 mg subcutaneous every 2 weeks cycles 3-6. Patients underwent Autologous Stem-Cell Transplantation after the completion of induction therapy (cycle 4) and consolidation therapy began 30-60 days after transplantation. After completion of consolidation therapy (cycle 6), all the patients received Lenalidomide 10 mg orally in 28-day maintenance cycles until disease progression or unacceptable toxicities. Patients in the D-VRd group also received maintenance therapy with subcutaneous Daratumumab 1800 mg subcutaneous every 4 weeks for at least 24 months and Daratumumab therapy was discontinued in patients who had a Complete Response or better and had sustained Minimal Residual Disease (MRD)–negative status (defined as absence of malignant cells at a sensitivity threshold of 10−5 or lower) for at least 12 months. The median age was 60 years and randomization was stratified according to the Stage (I, II, or III) and cytogenetic risk (standard risk or high risk, defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16] cytogenetic abnormality). The Primary end point was Progression Free Survival. Secondary end points included a Complete Response or better and Minimal Residual Disease negative status.

At a median follow-up of 47.5 months, at the first interim analysis, the risk of disease progression or death in the D-VRd group was significantly lower than the risk in the VRd group. The 4-year PFS was 84.3% in the D-VRd group and 67.7% in the VRd group (HR for disease progression or death=0.42; P<0.001). The percentage of patients with a Complete Response or better was higher in the D-VRd group than in the VRd group (87.9% versus 70.1%; P<0.001). The same was true with MRD-negative status (75.2% versus 47.5% respectively, P<0.001). Serious adverse events occurred in 57% of the patients in the D-VRd group and 49.3% of those in the VRd group. Treatment discontinuation due to adverse events however occurred less often in the quadruplet group.

The researchers concluded that the addition of subcutaneous Daratumumab to VRd induction and consolidation therapy and to Lenalidomide maintenance therapy conferred a significant and clinically meaningful benefit with respect to Progression Free Survival, Complete Response rate and MRD-negative status, with a favorable benefit–risk profile, among transplantation-eligible patients with newly diagnosed multiple myeloma.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. for the PERSEUS Trial Investigators. Published on December 12, 2023, at NEJM.org. DOI: 10.1056/NEJMoa2312054.

FDA Approves WELIREG® for Advanced Renal Cell Carcinoma

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SUMMARY: The FDA on December 14, 2023, approved Belzutifan (WELIREG®) for patients with advanced Renal Cell Carcinoma (RCC) following a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) inhibitor and a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor (VEGF-TKI). The American Cancer Society estimates that 81,800 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2023 and about 14,890 people will die from this disease. Clear cell Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer in adults. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five-year survival of patients with advanced RCC is about 14% and there is a significant need for improved therapies for this disease.

Patients with advanced RCC are often treated with immune checkpoint inhibitors and Vascular Endothelial Growth Factor Receptor (VEGFR) targeted Tyrosine Kinase Inhibitors, either in combination or sequentially. However upon progression on these therapies, there are limited treatment options and there is an unmet medical need.

The VHL (Von Hippel-Lindau) protein is a tumor suppressor gene located on the short arm of chromosome 3p. It is frequently mutated and inactivated in approximately 90% of clear cell Renal Cell Carcinomas (ccRCC). The VHL gene under normal conditions binds to Hypoxia-Inducible Factors (HIFs) and facilitates degradation of this factor. Under hypoxic conditions and in patients having biallelic loss of function and mutation of VHL genes, HIFs are not degraded. High HIF levels and subsequent overproduction of VEGF, PDGF and TGF-alpha, resulting in increased angiogenesis, increased tumor cell proliferation and survival, as well as metastasis.

Belzutifan (WELIREG®) is a a first-in-class, oral, HIF-2alfa inhibitor approved in the US for adult patients with Von Hippel-Lindau (VHL) disease who require therapy for associated Renal Cell Carcinoma (RCC), Central Nervous System (CNS) Hemangioblastomas, or Pancreatic NeuroEndocrine Tumors (pNET), not requiring immediate surgery. This approval was based on the Overall Response Rate (ORR) and Duration of Response (DOR) data from the Phase II LITESPARK-004 trial.

The present FDA approval was based on LITESPARK-005, which is a randomized, open-label, Phase III trial, in which Belzutifan was compared with Everolimus in pretreated advanced Renal Cell Carcinoma (RCC). In this study, 746 enrolled patients with metastatic clear cell RCC whose disease progressed after treatment with both an immune checkpoint inhibitor, such as a PD-1 or PD-L1 inhibitor, and VEGF-TKI, in sequence or in combination, were randomly assigned 1:1 to receive either Belzutifan 120 mg orally daily (N=374) or Everolimus 10 mg orally daily (N=372), until disease progression or unacceptable toxicity. The dual Primary endpoints were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary endpoints included Overall Response Rate (ORR) by BICR and Safety.

At the first pre-specified interim analysis at a median follow up of 18.4 months, Belzutifan significantly reduced the risk of disease progression or death by 25% compared to Everolimus (HR=0.75; P<0.001). The results at the second pre-specified interim analysis were consistent with first interim analysis. At a median follow-up of 25.7 months, Belzutifan significantly reduced the risk of disease progression or death by 26% compared to Everolimus (HR=0.74; P<0.001). The estimated 12-month PFS rate was 33.7% for patients who received Belzutifan versus 17.6% for patients who received Everolimus, and the estimated 18-month PFS rate was 22.5% and 9.0%, respectively. The Overall Survival data favored Belzutifan compared to Everolimus at both the first and second interim analysis, but did not reach statistical significance and will be tested at a subsequent analysis.

There was a statistically significant improvement in ORR at both the first and second interim analysis, and the ORR was 22.7% with a Complete Response rate 3.5% for patients who received Belzutifan versus an ORR of 3.5% with no patients achieving a Complete Response for patients who received Everolimus (P<0.00001). The time to response with Belzutifan was about three months. Quality of Life favored Belzutifan.

Treatment-related adverse events and in particular Grade 3 adverse events were similar in both treatment groups. Adverse events leading to treatment discontinuation occurred in 5.9% of patients who received Belzutifan and 14.7% among those who received Everolimus. The most common side effects associated with Belzutifan were anemia, fatigue, nausea, constipation, peripheral edema, dyspnea and arthralgia.

It was concluded that Belzutifan was associated with a statistically significant improvement in Progression Free Survival and Overall Response Rate compared to Everolimus in patients with advanced clear cell Renal Cell Carcinoma, after immune checkpoint and anti-angiogenic therapies. They added that this is the first Phase III trial to show positive results in advanced RCC following standard therapies and the first drug with a new mechanism of action to demonstrate efficacy in this group of patients.

Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Randomized open-label phase III LITESPARK-005 study. Albiges L, Rini BI, Peltola K, et al. DOI:https://doi.org/10.1016/j.annonc.2023.10.090. LBA88

Less Frequent Mammography after Curative Treatment in Older Women with Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

Currently, the major national health care organizations in the US have different recommendations for screening mammography which has led to some confusion and emotional counterarguments. These several different recommendations include 1) Annual screening at ages 40 to 84 years 2) Annual screening at ages 45 to 54 years and then biennially at ages 55 to 79 years 3) Biennial screening at ages 50 to 74 years.
Elderly women with a history of breast cancer have a higher risk for a second breast cancer diagnosis. However, appropriate mammographic surveillance methods for this patient group, remains unclear. The widespread practice of annual surveillance mammograms for an unspecified period of time after treatment for early breast cancer can be a significant burden of health care costs in the US.

Mammo-50 trial is a multicenter, randomized Phase III study conducted to assess annual mammography versus less frequent mammography for up to 9 years, in women 50 years or older at the time of their diagnosis with breast cancer. The goal of this study was to determine the optimum frequency and duration of mammographic surveillance. In this study 5,235 women were randomly assigned 1:1 to undergo annual mammograms (N=2618) or less frequent mammograms (N=2617). Less frequent mammography was defined as every 2 years in patients who underwent breast-conservation surgery (N=2099) and every 3 years in patients who had a mastectomy (N=518). Eligible enrolled patients were 50 years of age or older, had undergone curative-intent treatment for invasive or non-invasive breast cancer, and were 3 years post-surgery. Approximately 83% of women were aged 55-75 years, and 87% had invasive disease between the two cohorts. The compliance rates were 83% for the annual mammogram group and 69% for the less frequent mammography group. Approximately 35% of patients missed mammograms due to the COVID-19 pandemic. The Primary study outcomes were Breast Cancer-specific survival and cost effectiveness, whereas Secondary outcomes included Recurrence Free Interval and Overall Survival.

The researchers noted that the efficacy outcomes with regards to breast cancer-specific survival, 5-year recurrence-free interval and OS were similar between the two cohorts of patients. The breast cancer-specific survival at 5 years was 98.1% among patients in the annual mammography cohort and 98.3% among patients in the less frequent mammography cohort. The 5-year Recurrence Free interval rates were 94.1% for the annual mammography group and 94.5% among patients in the less frequent mammography cohort. The 5-year Overall Survival was 94.7% in the annual mammography cohort and 94.5% in the less frequent mammography cohort. Even though compliance in the less frequent mammography group was lower, a sensitivity analysis confirmed this had no effect on the outcomes.

It was concluded from this trial that less frequent mammograms were no worse than undergoing annual mammograms for this group of women,

Mammographic surveillance in early breast cancer patients aged 50 years or over: Results from the Mammo-50 non-inferiority trial of annual versus less frequent mammography. Dunn JA, Donnelly P, Elbeltagi N, et al. Presented at SABCS 2023. December 5-9, 2023. San Antonio, TX. Abstract GS03-02.

Biomarker Driven ELAHERE® in FR alpha-Positive, Platinum-Resistant Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 19,710 women will be diagnosed with ovarian cancer in 2023, and 13,270 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. About 85% of all ovarian cancers are epithelial in origin, and 70% of all epithelial ovarian cancers are High-Grade serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival (OS) rate of about 20-30%. Treatment options for patients with platinum-resistant ovarian cancer are limited, and patients are often treated with single-agent chemotherapy, with an Overall Response Rate (ORR) of between 4% and 13%, short duration of response, and significant toxicities.

Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha (FR alpha), and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue.

ELAHERE® (Mirvetuximab soravtansine-gynx) is a first-in-class Antibody Drug Conjugate (ADC), directed against FR alpha, a cell-surface protein highly expressed in ovarian cancer. It is comprised of a Folate Receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, which is a potent tubulin inhibitor, disrupting microtubule formation, and thereby designed to kill the targeted cancer cells. Microtubules are major components of the cytoskeleton that give shape and structure to cells. ELAHERE® is the first FDA approved ADC for platinum-resistant disease. In the single-arm SORAYA trial, ELAHERE® demonstrated an ORR of 31.7% and median Duration of Response of 6.9 months, in patients with platinum-resistant ovarian cancer, and prior Bevacizumab exposure. These response rates were consistently seen regardless of the number of prior therapies or the use of a prior PARP inhibitor. As a result, the FDA in November 2022 granted accelerated approval to ELAHERE®.

MIRASOL is a confirmatory randomized Phase III trial, conducted to evaluate the efficacy and safety of ELAHERE® versus Standard-of-Care chemotherapy, in patients with pretreated, platinum-resistant ovarian, peritoneal, or fallopian tube cancer, whose tumors express high levels of FR alpha. In this study, 453 eligible patients (N=453) were randomized 1:1 to receive ELAHERE® 6 mg/kg (based on adjusted ideal body weight) IV infusion once every three weeks, until disease progression or unacceptable toxicity (N=227), or investigators choice of single-agent chemotherapy – Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan (N=226)). Both treatment groups were well balanced. Approximately 13% of patients had BRCA mutations, 14% of patients had one prior line of therapy, 39% had two prior lines and 47% had three prior lines of therapy. About 62% received prior Bevacizumab and 55% received prior therapy with PARP inhibitors. The Primary efficacy endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Response Rate (ORR), Overall Survival (OS), and Patient-Reported Outcomes in hierarchical order, as well as Safety and tolerability. The median follow up was 13.1 months.

This study met its Primary and key Secondary endpoints with statistically significant improvement in PFS, ORR and OS. The PFS in the ELAHERE® group was 5.62 months compared to 3.98 months in the chemotherapy group (HR=0.65; P<0.0001). The ORR was also higher in the ELAHERE® group at 42% compared with 16% in the chemotherapy group (P<0.0001). The median Overall Survival rate was 16.46 months among patients who received ELAHERE® compared with 12.75 months among those who received single-agent chemotherapy (HR=0.67; P=0.005). The PFS and OS outcomes favored the ELAHERE® group, irrespective of prior exposure to Bevacizumab. Treatment with ELAHERE® was associated with a lower rate of Grade 3 or more Adverse Events and a lower discontinuation rate (9% compared with 16% for the chemotherapy group). The most common adverse reactions including laboratory abnormalities associated with ELAHERE® were vision impairment, keratopathy, fatigue, nausea, peripheral neuropathy, increase in ALT and AST and cytopenias. Product labeling includes a boxed warning for ocular toxicity. The ocular events were reversible and primarily included low-grade blurred vision and keratopathy, which were managed with protocol-defined dose modifications. Approximately 60% of patients with symptoms had resolution prior to their next cycle of treatment, and less than 1% of patients discontinued therapy due to an ocular event.

It was concluded that treatment with ELAHERE® demonstrated a statistically significant improvement in Progression Free Survival and Overall survival, compared to chemotherapy, in patients with platinum-resistant ovarian cancer and high FR alpha expression, independent of Bevacizumab use, and may be the new standard-of-care for this patient group. ELAHERE® is the first FDA-approved Antibody Drug Conjugate and biomarker directed therapy for ovarian cancer, since the approval of PARP inhibitors.

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer. Moore KN, Angelergues A, Konecny GE, et al. N. Engl J Med 2023;389:2162-2174

Omitting Adjuvant Radiation Therapy in Younger Low Risk Postmenopausal Patients

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor-positive (HR-positive), HER2-negative breast cancer is the most frequently diagnosed molecular subtype.

Patient undergoing breast conserving surgery, often receive adjuvant breast radiation therapy to reduce the risk of local recurrence. Radiation therapy however is inconvenient, expensive and can be associated with acute and late toxicities. Several previously published trials explored the omission of radiotherapy in low risk patients, following Breast Conservative Surgery. In the CALGB 9343 trial involving women 70 years or older with Stage I, ER-positive breast cancer, treated with Breast Conservative Surgery, locoregional recurrence at 10 years was 10% among those randomly assigned to omission of radiotherapy group and 2% among those assigned to radiotherapy. Similarly, in the PRIME II trial, women 65 years and older with node-negative tumors 3 cm or smaller in size, treated with Breast Conservative Surgery and Endocrine Therapy, had a local recurrence rate of 10% at 10 years when radiation was omitted versus 1% among those assigned to radiotherapy. In the LUMINA trial, women 55 years of age and over with low grade Luminal A breast cancer following Breast Conserving Surgery, Endocrine Therapy and without radiotherapy, had a local recurrence rate of 2.3% at 5 years. These trials provided a new option to elderly patients who wished to avoid radiotherapy

The IDEA (Individualized Decisions for Endocrine therapy Alone) study is a prospective, multicenter cohort trial, initiated at 13 US institutions in 2015. This single-arm study was designed to explore the feasibility of omitting radiotherapy in younger postmenopausal patients with early-stage breast cancer, based on genomic assay, in addition to clinicopathologic risk factors. The IDEA study was inspired by the desire to expand treatment options for de-escalation of therapy for patients with low molecular risk early stage breast cancer, based on prospective clinical data. In this study 200 eligible patients (N=200) were enrolled. This trial included postmenopausal patients 50-69 years of age, with pT1N0 unifocal invasive breast cancer, with margins 2 mm or more after lumpectomy, whose tumors were ER-positive, PR-positive and HER2-negative, with Oncotype DX 21-gene recurrence score of 18 or less. Patients consented to at least 5 years of Endocrine Therapy after lumpectomy and omitting radiotherapy. The mean age was 62 years, mean tumor size was 10 mm and mean 21-gene recurrence score was 11. Histology was ductal in 85% and lobular in 10%, 42.5% had Grade I, 54.5% had Grade II, and 3% had Grade III tumors, respectively, and lymphovascular invasion was present in 14% of tumors. Patients with bilateral disease, a previous personal history of breast cancer, previous radiotherapy to the breast region, or a known carrier of a mutation that predisposes toward breast cancer development (including BRCA-1 and BRCA-2), were excluded. The Primary end point was the rate of locoregional recurrence, 5 years after Breast Conserving Surgery.

With a clinical follow up of at least 56 months among 186 patients, the Overall Survival (OS) and Breast Cancer-Specific Survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99%. Crude rates of Ipsilateral Breast Events for the entire follow up period for patients age 50-59 years and age 60-69 years were 3.3% and 3.6%, respectively, and crude rates of overall recurrence were 5.0% and 3.6%, respectively. No distant recurrences were observed.

It was concluded from this study that high disease control can be accomplished at 5 years after omission of radiotherapy, in postmenopausal patients with pT1N0 unifocal invasive breast cancer with favorable biologic features. The authors added that the IDEA study is the first prospective trial to incorporate a genomic assay of low molecular risk, to identify appropriate candidates for omission of breast radiotherapy.

Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA. Jagsi R, Griffith KA, Harris EE, et al. Published online December 07, 2023. DOI: 10.1200/JCO.23.02270 Journal of Clinical Oncology.

FDA Approves KEYTRUDA® with Chemotherapy for HER2-Negative Gastric or GE Junction Adenocarcinoma

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SUMMARY: The FDA on November 16, 2023, approved Pembrolizumab (KEYTRUDA®) with Fluoropyrimidine and Platinum containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma. The American Cancer Society estimates that in the US about 26,500 new Gastric cancer cases will be diagnosed in 2023 and about 11,130 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine and, if appropriate, HER2/neu-targeted therapy. This can however be associated with significant toxicities impacting patient’s quality of life. The efficacy of PD-1 inhibitors in combination with chemotherapy has been demonstrated in Gastric and GastroEsophageal cancer.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

The present FDA approval was based on KEYNOTE-859, which is a double-blind, placebo-controlled, randomized Phase III trial, conducted to evaluate the benefit of adding Pembrolizumab to Fluoropyrimidine and Platinum-containing doublet chemotherapy in patients with advanced HER2-negative Gastric or GastroEsophageal cancer. In this study, 1,579 patients with locally advanced or metastatic HER2-negative Gastric or GastroEsophageal adenocarcinoma, with known a PD-L1 Combined Positive Score (CPS), were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV (N=790) or placebo (N=789), every 3 weeks for 35 cycles or less, given along with investigator’s choice of 5-FU plus Cisplatin or Capecitabine plus Oxaliplatin (CAPOX). Baseline characteristics were balanced between treatment groups and randomization was stratified by region, PD-L1 CPS (less than 1 versus 1 or more), and choice of chemotherapy. At baseline, 78% of patients had PD-L1 CPS 1 or more, while 35% had tumors with CPS 10 or more. The Primary end point was Overall Survival (OS) by blinded Independent Central Review. Secondary end points included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR) and Safety. The researchers provided the data from the interim analysis, at a median follow up of 31.0 months.

The median Overall Survival was 12.9 months with Pembrolizumab plus chemotherapy versus 11.5 months with chemotherapy alone (HR=0.78, P<0.0001). The median PFS was 6.9 months versus 5.6 months, respectively (HR=0.76, P<0.0001). The benefit with Pembrolizumab was consistent across subgroups, including those by PD-L1 CPS. The risk reduction was especially notable among patients with MicroSatellite Instability (MSI)-High status, who had a 66% relative reduction in the risk of death, and patients with PD-L1 CPS 10 or more, whose risk was reduced by 36%. The Objective Response Rate was 51.3% in the Pembrolizumab group and 42.0% in the control group (P=0.00009), and the median Duration of Response was 8.0 months versus 5.7 months, respectively. Immune-related toxicities, especially hypothyroidism, were more common with Pembrolizumab plus chemotherapy and no new safety signals were seen.

It was concluded that treatment with Pembrolizumab plus chemotherapy resulted in a statistically significant and clinically meaningful improvement in Overall Survival, Progression Free Survival and Objective Response Rate, among patients with locally advanced or metastatic, HER2-negative Gastric or GastroEsophageal adenocarcinoma of any PD-L1 expression level, thus providing a new treatment option for this patient group.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Rha SY, Oh D-Y, Yanez P, et al. The Lancet Oncology 2023; 24:1181-1195.

FDA Approves XTANDI® for Non-Metastatic Castrate-Sensitive Prostate Cancer with Biochemical Recurrence

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SUMMARY: The FDA on November 16, 2023, approved Enzalutamide (XTANDI®) for non-metastatic Castration-Sensitive Prostate Cancer (nmCSPC) with biochemical recurrence, at high risk for metastasis. 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 288,300 new cases of Prostate cancer will be diagnosed in 2023 and 34,700 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer, and is the first treatment intervention.

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. 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. Rising PSA is therefore a sign of recurrent disease. Patients with biochemically relapsed prostate cancer following local therapy, and a short PSA doubling time, are at risk for distant metastases.

Enzalutamide is a potent oral Androgen Receptor signaling inhibitor with demonstrated efficacy in patients with both localized and advanced prostate cancer. The present FDA approval is based on results from the EMBARK trial.

EMBARK is a randomized, double-blind, placebo-controlled, multi-national, Phase III trial, conducted to evaluate the efficacy and safety of Enzalutamide plus Leuprolide and Enzalutamide monotherapy, as compared with Leuprolide alone, in patients with non-metastatic Hormone/Castration-Sensitive Prostate Cancer (nmHSPC or nmCSPC) prostate cancer, who have had high-risk biochemical recurrence. In this study, a total of 1068 eligible patients were randomly assigned 1:1:1 to receive Enzalutamide at 160 mg orally once daily plus Leuprolide every 12 weeks (N=355), single agent Enzalutamide at 160 mg orally once daily (N=355) or Leuprolide alone (N=358). All patients had received prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent. High risk disease was defined as a PSA doubling time of 9 months or less and a PSA level of 2 ng/ml above nadir after radiation therapy, or 1 ng/ml or more after radical prostatectomy with or without postoperative radiation therapy. The baseline characteristics were well balanced among the treatment groups. The median age was 69 years, the median PSA doubling time was 4.9 months and the median PSA level was 5.2 ng/ml. The Primary end point was Metastasis-Free Survival (MFS), as assessed by Blinded Independent Central Review (BICR) in the combination group, as compared with the Leuprolide-alone group. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death due to any cause, whichever occurred first. A key Secondary end point was Metastasis-Free Survival in the Enzalutamide monotherapy group, as compared with the Leuprolide-alone group. Other Secondary end points were Patient-Reported Outcomes and Safety.

At a median follow up 60.7 months, the 5 year MFS was 87.3% in the Enzalutamide combination group and 71.4% in the Leuprolide-alone group (HR for metastasis or death 0.42; P<0.001). This represented a 58% lower risk of metastasis or death in the combination group than in the leuprolide-alone group. The 5 year MFS with Enzalutamide monotherapy versus Leuprolide alone was 80% versus 71.4% respectively (HR=0.63; P=0.005), suggesting a 37% lower risk of metastasis or death in the Enzalutamide monotherapy group than in the Leuprolide-alone group. At the time of this analysis, Overall Survival data were immature. No new safety signals were reported, and there was no substantial difference in Quality of Life measures between the treatment groups.

It was concluded that in patients with prostate cancer with high-risk biochemical recurrence, both Enzalutamide plus Leuprolide and Enzalutamide monotherapy resulted in significantly longer Metastasis-Free Survival and a longer time to PSA progression and receipt of next antineoplastic therapy, compared to Leuprolide alone, while maintaining overall Quality of Life.

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. N Engl J Med. 2023;389:1453-1465.