Clinical Trials: From the Editor
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PI3K/AKT/mTOR Inhibitors for Prostate Cancer – Finally Hints of a Breakthrough
Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has been strongly linked with prostate cancer progression and metastatic potential.1 Loss of the inhibitory phosphatase, PTEN, leading to hyperactivation of PI3K/AKT/mTOR oncogenic signaling, occurs in 40-50% of metastatic castration-resistant prostate cancer.1,2 Not surprising is the fact that PTEN loss in patients with metastatic castration-resistant prostate cancer is associated with a worse prognosis and less benefit from androgen receptor (AR) blockade.3 Likewise, PTEN loss and subsequent Akt activation confer radiation4 and chemotherapy5, 6 resistance.
Cabozantinib for Prostate Cancer - A Renewed Hope
Cabozantinib, an oral tyrosine kinase inhibitor against MET and vascular endothelial growth factor receptor 2 (VEGFR2), is an agent that was initially met with enormous enthusiasm by the prostate cancer community. The early data showed dramatic bone scan responses, where bone metastases would almost magically disappear after cabozantinib treatment on subsequent restaging bone scans. As this was an unfamiliar, yet welcome phenomenon, the field eagerly began working on the development of this agent.
Erdafitinib, Potential for Expanding Indications for the Future
It has now been approximately a year and a half since the United States Food and Drug Administration (FDA) granted accelerated approval to erdafitinib for patients with locally advanced or metastatic urothelial carcinoma, with susceptible fibroblast growth factor receptor 3 (FGFR3) or FGFR2 genetic alterations after progression during or following platinum chemotherapy.1 The label is inclusive of patients within 12 months of neoadjuvant or adjuvant platinum chemotherapy. Additionally, the label includes companion diagnostic information for a jointly approved therascreen® FGFR RGQ RT-PCR kit, for this specific therapeutic indication.
What’s the Rationale for Adding PARP Inhibitors to Androgen Pathway Inhibitors for Patients with Prostate Cancer?
The TRITON2 trial demonstrated a 43.5% objective response rate with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious BRCA1 or BRCA2 alteration.3 This trial led to the United States Food and Drug Administration (FDA) granting accelerated approval to rucaparib for the
Prostate Cancer Imaging Is Changing Rapidly – What More Should Be Done with Fluciclovine (Axumin®) PET/CT Imaging?
Fluciclovine PET imaging is the most sensitive imaging modality we have to date that is United States Food and Drug Administration (FDA) approved and available for widespread use. Fluciclovine is a synthetic amino acid that is uptaken by amino acid transporters that are upregulated in many cancer cells, including prostate cancer. A key advantage of fluciclovine is that it has low renal excretion, which is ideal for imaging the pelvis. The sensitivity and specificity of PET imaging with fluciclovine are superior to choline in a direct comparative trial of patients in the biochemically recurrent prostate cancer disease state.1 The FDA approval is in men with suspected prostate cancer recurrence based on elevated prostate-specific antigen (PSA) levels following prior treatment.2
Improving on Cabazitaxel Chemotherapy for Metastatic Prostate Cancer – Studying Novel Combinations
For men with metastatic castration-resistant prostate cancer, there are limited options for treatment after progression on docetaxel chemotherapy. Fortunately, cabazitaxel is another taxane chemotherapy that offers a survival benefit in the post-docetaxel setting over mitoxantrone in the TROPIC trial.1 The initial concern was a 7.5% febrile neutropenia rate and a 4.9% toxic death rate. However, this concern has been ameliorated with increased utilization of growth factor prophylaxis, and the PROSELICA trial showed non-inferiority of 20 mg/m2 dosing compared with the 25 mg/m2 dosing in regards to overall survival, with much lower toxicity.2
Combination Therapy with Docetaxel for Metastatic Castration-Resistant Prostate Cancer – New Drugs with New Promise?
When docetaxel first emerged on the prostate cancer scene, the world celebrated our first agent that offered an overall survival benefit for patients with metastatic castration-resistant prostate cancer.1,2 Although, there are now many more agents regulatory approved for metastatic castration-resistant prostate cancer, docetaxel remains an important “tool in our toolbox” in our attempts to improve survival and quality of life for our patients.
For the next decade after docetaxel’s approval for metastatic castration-resistant prostate cancer, the field saw multiple combination therapy trials with docetaxel without any success. This included multiple randomized, phase 3, controlled trials, with no therapeutic agents affording the ability to offer a survival improvement when added to docetaxel.3-11
The Oligometastatic-Directed Therapy Trend in Prostate Cancer: Are We Being Precocious or Premature?
The identification of oligometastatic prostate cancer is becoming more feasible due to improved imaging technologies. For example, 11C-choline PET/CT imaging has approximately 50% sensitivity for detection at a prostate-specific antigen (PSA) level of 1.5-2.0 ng/mL.1 However, 11C-choline PET/CT imaging is not widely available, as it requires an on-site cyclotron for production. Prostate-specific membrane antigen (PSMA) small molecules tagged with either 68Gallium or 18Fluoride are also highly sensitive with detection felt to begin at PSA levels of 0.2-0.5 ng/mL.2-4 PSMA PET imaging is also not yet widely available. Fluciclovine PET/CT imaging was recently approved by the United States Food and Drug Administration (FDA) for the detection of recurrent prostate cancer. Fluciclovine PET/CT carries the ability to detect prostate cancer starting at a level of around 0.5 ng/mL,5-10 and it is becoming widely available for use.
Are Chimeric Antigen Receptor (CAR)-T Cells Ready for Prime Time in Prostate Cancer?
COVID-19 has affected everything we do in medicine and science. This certainly includes cancer research, and many clinical trials have placed temporary holds on patient accrual to reserve hospital/intensive care unit beds, preserve personal protective equipment, and limit person-to-person contact. However, we must be optimistic and start to plan for a future when the COVID-19 pandemic calms down. The first wave of clinical trials to reopen must importantly take into account the risk/benefit ratio for the patient.
Neuroendocrine Carcinomas of the Genitourinary Tract – Treatment Options Are Desperately Needed… Even During the COVID-19 Pandemic
Enfortumab Vedotin – Changing the Way We Think About Urothelial Cancer
The United States Food and Drug Administration (FDA) granted accelerated approval to enfortumab vedotin (Padcev®, manufactured and marketed by Astellas Pharma US, Inc., Northbrook, Illinois 60062; distributed and marketed by Seattle Genetics, Inc., Bothell, WA 98021) on December 18, 2019, for patients with locally advanced or metastatic urothelial cancer who have previously received platinum chemotherapy and a PD-L1 inhibitor. Two years ago, I briefly mentioned enfortumab vedotin in a Clinical Trials Portal article focused on discussing the promising Antibody Drug Conjugate (ADC) class of drugs.
Neoadjuvant Systemic Therapy for Prostate Cancer: If a PUNCH Is Good, What Will It Take to Score a Knockout?
With all the randomized trial data supporting a survival benefit of androgen deprivation therapy with primary radiation to the prostate, it is unfortunate that the same results have not been achieved in combination with radical prostatectomy. The data has been replicated in multiple randomized controlled trials, confirming that addition of androgen deprivation therapy in a neoadjuvant, concurrent and adjuvant fashion to definitive primary local radiation leads to a survival benefit for men with high-risk prostate cancer.1
177Lutetium-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer; Randomized Controlled Phase 3 Trial Data is Pending and Novel Combinations are Being Tested
Is Chemoimmunotherapy Prime Time for First-Line Metastatic Urothelial Carcinoma?
Results from a first-line chemoimmunotherapy trial in patients with metastatic urothelial carcinoma were recently presented at the 2019 European Society of Medical Oncology (ESMO) Congress.1 These early results from the IMvigor 130 trial provide the first hints that novel combination therapy offers benefit for patients with locally advanced or metastatic urothelial carcinoma. This trial randomized patients to atezolizumab plus platinum/gemcitabine (Arm A) vs. atezolizumab monotherapy (Arm B) vs. placebo plus platinum/gemcitabine (Arm C).
The CARD Trial Creates a New Standard… For Certain Patients
At the European Society of Medical Oncology (ESMO) Congress 2019, the randomized phase 3 CARD trial was presented, with a simultaneous publication in the New England Journal of Medicine.1 This trial randomized 255 men with metastatic castration-resistant prostate cancer in a 1:1 fashion, who previously received docetaxel and an Androgen-Signaling-targeted Inhibitor (ASI), either abiraterone or enzalutamide, to cabazitaxel 25 mg/m2 plus prednisone and granulocyte colony-stimulating factor or the other ASI.
What Works for Breast Cancer Should Work for Prostate Cancer, Right?
Is HER2 Still a Worthwhile Therapeutic Target for Urothelial Bladder Cancer?
Polycomb Complex Enhancer of Zeste 2 (EZH2), a Regulator of Lineage Reprogramming and a New Drug Target
Heating Things Up in a Volatile Marriage…Bispecific Antibody Therapy in Prostate Cancer
Enzalutamide and Apalutamide Now Offer Survival Benefit for Patients with Metastatic Castration-Sensitive Prostate Cancer, But How Do Things Change Now and What Should We Be Doing Next?
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