ESMO 2021

(UroToday.com) Since 2015, several phase 3 randomized controlled trials have demonstrated that adding either androgen pathway inhibitors or chemotherapy to testosterone suppression can prolong overall survival for men diagnosed with metastatic hormone-sensitive metastatic prostate cancer (mHSPC). The STAMPEDE study has specifically demonstrated a survival advantage in mHSPC with the addition of the androgen synthesis inhibitor abiraterone acetate. Based on observations from STAMPEDE that radiation therapy may reduce treatment failure rates in locally advanced prostate cancers as well as preclinical data suggesting that stereotactic body radiotherapy (SBRT) can induce expression of PD-L1 on tumor and immune cells, the authors of this abstract tested the hypothesis that the combination of testosterone suppression, abiraterone acetate, SBRT and the anti-PD-L1 drug atezolizumab may together exert synergistic effects to improve outcomes in men with mHSPC.

(UroToday.com) Poly (ADP-ribose) polymerase inhibitors provide clinical benefit across multiple cancers with germline or somatic alterations in the BRCA1 and BRCA2 genes, as well as other select genes within the homologous recombination DNA repair pathway. The PARP inhibitors olaparib and rucaparib are approved for use in metastatic castration-resistant prostate cancer (mCRPC) in patients harboring certain genomic alterations in the DNA damage repair pathway. Talazoparib is another PARP inhibitor, which in a phase 2 study (TALAPRO-1) demonstrated anti-tumor activity in men with mCRPC harboring alterations in homologous recombination repair. Interestingly, androgen pathway inhibitors such as enzalutamide have been shown to downregulate the expression of homologous recombination repair genes, resulting in a BRCA-like phenotype in cancer cells. To test the hypothesis that the addition of PARP inhibition to enzalutamide can improve clinical outcomes of enzalutamide alone, Dr. Aggarwal and colleagues presented the TALAPRO-2 trial.

(UroToday.com) Lutetium-177 is a radioligand that when bound to a prostate-specific membrane antigen (PSMA) targeting molecule delivers beta-particle radiation to PSMA-expressing cells and their local microenvironment. This therapy depends on prostate cancer cell surface expression of PSMA, which may be altered by androgen pathway inhibitors. To optimize the utility of this treatment modality in metastatic hormone-sensitive prostate cancer (mHSPC), the PSMAddition trial (NCT04720157) was designed.

(UroToday.com) Treatment options for men with metastatic castration resistant prostate cancer (mCRPC) are limited beyond taxane chemotherapy and second-generation androgen pathway inhibitors. Moreover, resistance to these agents is associated with the emergence of small cell neuroendocrine prostate cancer in a subset of patients (tSCNC), portending poor prognosis. Additional therapeutic options are required for patients who have progressed on the multiple therapies approved in mCRPC, especially for patients with tSCNC.

(UroToday.com) Lutetium-177 is a radioligand that when bound to a prostate-specific membrane antigen (PSMA) targeting molecule delivers beta-particle radiation to PSMA-expressing cells and their local microenvironment. This therapy depends on prostate cancer cell surface expression of PSMA. The phase 3 VISION trial demonstrated overall survival benefit with this treatment modality in mCRPC patients who had progressed on taxane chemotherapy as well as androgen pathway inhibition. In this abstract, Dr. Morris and colleagues present the PSMAfore trial (NCT04689828), testing Lutetium-177 in mCRPC prior to taxane chemotherapy.

(UroToday.com) The advent of positron emission tomography using radiolabeled prostate-specific membrane antigen (PSMA) ligands, called PSMA-PET, is rapidly changing prostate cancer staging imaging. However, as all published randomized clinical trials and studies to date have utilized conventional imaging, the impact that PSMA-PET clinical upstaging should have on treatment is unknown. To address this question, the authors present the PRIMORDIUM trial in progress (NCT04557059), which specifically evaluates the benefit of adding the androgen receptor inhibitor apalutamide to testosterone suppression and radiotherapy in patients experiencing a “high-risk” biochemical recurrence after radical prostatectomy.

(UroToday.com) The NIVOREN GETUF AFU 26 study is a French multi-center prospective study to evaluate the safety and efficacy of the anti-PD-1 checkpoint agent nivolumab in a “real world” setting after failure of 1-2 tyrosine kinase inhibitor in metastatic renal cell carcinoma (mRCC). As antibiotic use around the time of starting immune checkpoint blockade has been associated with reduced efficacy in multiple cancer types, Dr. Derosa and colleagues identified patients from the NIVOREN study who received antibiotics between 60 days prior to starting therapy to 42 days after starting nivolumab and assessed the impact on clinical outcomes and toxicities.

(UroToday.com) VEGF-targeting therapies have been shown to induce hypoxia in preclinical models of renal cell carcinoma (RCC), thus activating signaling through the hypoxia-inducible factors. In this phase 2 study, Dr. McDermott and colleagues tested the hypothesis that dual inhibition of both VEGF and downstream HIF signaling would provide anti-tumor for patients with clear cell RCC.

(UroToday.com)Stage 3 urothelial cancer has a poor prognosis, which can be improved modestly with neoadjuvant cisplatin chemotherapy prior to radical cystectomy. However, options to improve prognosis in patients that are to receive cisplatin are lacking. The NABUCCO trial, cohort 1, involved treating stage 3 urothelial cancer patient with two doses of neoadjuvant ipilimumab (3 mg/kg) with a dose of nivolumab 1 mg/kg followed by a fourth treatment dose with nivolumab 3 mg/kg. This approach resulted in a 46% pathologic complete response rate (pCR) at the time of cystectomy, and 58% of patients had either pCR or non-invasive disease.¹

(UroToday.com) Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is a standard of care for non-metastatic muscle-invasive bladder cancer (MIBC). However, up to half of patients are not eligible for cisplatin-based chemotherapy. Neoadjuvant immune checkpoint inhibitors have shown anti-tumor activity in MIBC in multiple studies, both as monotherapy and in combination with chemotherapy. In this presentation, Dr. Nieves Martinez Chanza presented preliminary results from the AURA study, which studied the pathologic complete response rate with the addition of avelumab to neoadjuvant therapy in both cisplatin eligible and cisplatin-ineligible patients with MIBC.

(UroToday.com)Cisplatin-based chemotherapy is associated with improved responses and more durable outcomes than carboplatin in mUC, though the mechanisms for this are poorly characterized. An exploratory subset analysis of the IMvigor130 trial suggested that the addition of atezolizumab to cisplatin-based chemotherapy had more efficacy (hazard ratio for overall survival 0.73 (0.54 – 0.98) with cisplatin versus 0.91 (0.74-1.10) with carboplatin in cisplatin-treated patients rather than carboplatin treated patients. Dr. Galsky and colleagues hypothesized that perhaps cisplatin is associated with more favorable immunomodulatory effects that predispose tumors to greater response with immune checkpoint blockade.

(UroToday.com) In this presentation, Dr. Mozzi Etemadi discussed how computer programs, often referred to as artificial intelligence, can be used for cancer-based applications such as cancer screening.

(UroToday.com) In this presentation, Mr. Geissler, a long-time cancer survivor and patient advocate discussed how qualitative data from patients can strengthen cancer research. He began by describing the difficult trade-offs that are often the norm for cancer patients: choosing between either proven or unknown therapies that have a range of side effects that can range from bad to ugly. Researchers and institutions can utilize the unique insights of the patient community to further understand these trade-offs. Patients can enunciate what true “unmet needs” are in a disease, and what they find valuable. Discussing these perspectives can help identify information gaps that hinder informed decision-making, understand how diagnostics and side effects impact quality of life, and what other practice challenges exist in cancer care.

(UroToday.com) The Earlier Treatment in Prostate Cancer “How can we maximize the therapeutic index?” educational session at the European Society for Medical Oncology (ESMO) 2021 congress included a presentation by Dr. Heather Payne discussing quality of life and long-term comorbidities. Dr. Payne started by highlighting what quality of life means for our patients. Indeed, quality of life has multiple definitions, including the patient’s subjective report of their health status, their overall enjoyment of life, a measure of an individual’s sense of well-being and ability to carry out various activities, and the extent to which hopes and ambitions are matched by experience. Quality of life also has multiple domains, including physical, emotional/psychological, social functioning, level of independence, environmental (ie. financial resources, home, freedom), spirituality/religion, and others.

(UroToday.com) In the Controversy session of the European Society for Medical Oncology (ESMO) Annual Congress, Dr. Karim Fizazi and Dr. Ronald De Wit debated the question of whether enhanced androgen signaling inhibition should be the treatment of choice for treatment of metastatic castration sensitive prostate cancer (mCSPC) rather than docetaxel. Presenting first, Dr. Fizazi took the position that androgen signaling inhibition should be the treatment of choice, though he emphasized that potentially these approaches should be considered in combination.

(UroToday.com) In the Controversy session of the European Society for Medical Oncology (ESMO) Annual Congress, Dr. Karim Fizazi and Dr. Ronald De Wit debated the question of whether enhanced androgen signaling inhibition should be the treatment of choice for treatment of metastatic castration sensitive prostate cancer (mCSPC) rather than docetaxel. Presenting second, Dr. de Wit supported the use of docetaxel.

(UroToday.com) The European Society of Medical Oncology (ESMO) 2021 annual congress included a controversial session highlighting ‘Are adjuvant immune checkpoint inhibitors a standard of care for operable high-risk urothelial and kidney cancer?’ Dr. Michiel van der Heijden discussed that no, adjuvant immune checkpoint inhibitors are not standard of care. Dr. van der Heijden started by highlighting that spring 2021 was a happy time: the daily COVID numbers were decreasing, KEYNOTE-564 was presented at ASCO, and CheckMate 274 was published in the New England Journal of Medicine.¹ Taking a step back, it is important to remember that the goal of adjuvant therapy is to prevent disease recurrence and death, with the knowledge that a proportion of patients will be treated for a disease that was cured with surgery alone. As such, disease-free survival does not necessarily mean a survival benefit just that the time to disease recurrence was delayed.

(UroToday.com) The European Society of Medical Oncology (ESMO) 2021 annual congress included a controversial session highlighting ‘Are adjuvant immune checkpoint inhibitors a standard of care for operable high-risk urothelial and kidney cancer?’ Dr. Thomas Powles discussed that yes, adjuvant immune checkpoint inhibitors are standard of care. At the moment, there is no approved neoadjuvant or adjuvant therapy for patients with high-risk kidney cancer, but there are several scoring systems to risk-stratify patients. The KEYNOTE-564 trial¹ is the first adjuvant checkpoint inhibitor in the adjuvant disease space. Patients randomized to pembrolizumab had a significant disease-free survival benefit compared to those treated with placebo in the intention-to-treat population (HR 0.68, 95% CI 0.53-0.87):

(UroToday.com) The Earlier Treatment in Prostate Cancer “How can we maximize the therapeutic index?” educational session at the European Society of Medical Oncology’s (ESMO) 2021 congress included a presentation by Dr. Piet Ost discussing the role of imaging in selecting treatment. Dr. Ost notes that it is important to highlight that the Will Rogers phenomenon is present in prostate cancer. For example, high-risk localized prostate cancer patients that are negative with conventional imaging will have a proportion of patients that will be PET/CT positive and move to the oligometastatic cohort of patients. Thus, this shift will improve outcomes of the localized high-risk patients by removing those that are truly oligometastatic, but also improving outcomes of metastatic patients by adding low-volume oligometastatic patients to this group. As such, these are artificial improvements in outcomes-based novel imaging leading to stage migration.

(UroToday.com) The Earlier Treatment in Prostate Cancer “How can we maximize the therapeutic index?” educational session at the European Society of Medical Oncology’s (ESMO) 2021 congress included a presentation by Nicolas Mottet discussing evidence-based treatment options in biochemically relapsed prostate cancer. Dr. Mottet notes that the definition of relapse after external beam radiotherapy is the nadir + 2 ng/mL, with the rationale for this being that it was the best definition to predict further metastases. It was initially based on the Phoenix consensus but later was considered as the main clinical definition of relapse. With regards to relapse after radical prostatectomy, Dr. Mottet notes that there is a major difference between PSA relapse (any PSA rise following an undetectable level) and a clinically significant PSA rise, which is the best predictor of further metastases. Post-radical prostatectomy, the definition of relapse is no longer a PSA of 0.2 ng/mL and rising. Currently, following an undetectable PSA (<0.1 ng/mL), the best PSA threshold to define a relapse is 0.4 ng/mL and rising (since 2018 EAU-ESTRO-SIOG-ESUR guideline), given that this is the best correlation with systemic progression; this definition has also been adapted as a consensus statement by ASCO. The threshold of PSA > 0.4 ng/mL and rising is the most clinically relevant threshold, but it is not the threshold to define relapse, and it is not the threshold to consider salvage treatment.