ASCO 2020

(UroToday.com) In this study, Atish Choudhury and colleagues present the rationale and design for a phase 2 study of M6620, an inhibitor of the ATR kinase, in combination with carboplatin for patients with metastatic castration-resistant prostate cancer (mCRPC).

(UroToday.com) Prostate cancer is the most common non-cutaneous cancer diagnosed in men. All men with metastatic prostate cancer, as well as selected other patients with specific family histories, are recommended to undergo germline genetic testing. Given global limitations on genetic counseling services, this study designed an intervention to have medical oncologists perform pre-genetic testing counseling, arrange genetic testing, and provide initial results. The primary outcome of the intervention was clinician and patient satisfaction, with secondary outcomes of resource allocation and patient uptake of genetic counseling.

(UroToday.com) In this presentation, David R. Wise, MD, PhD, reviewed three presentations in prostate cancer from this conference.

Abstract 5500 – TheraP: A randomized phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel: Initial results (ANZUP protocol 1603)

Prostate cancers express the PSMA molecule on their surface, which has been exploited for targeted therapy. Prior clinical data has shown that the 177Lu-PSMA-617 molecule (LuPSMA), which delivers beta radiation to target cells causing cell death, has encouraging clinical activity from non-randomized studies in mCRPC. Specifically, a phase II study showed 64% of men experienced a 50% reduction in PSA on treatment, with relatively low toxicity. This abstract presented the first randomized study of LuPSMA relative to the standard of care option cabazitaxel in mCRPC. The primary endpoint was the rate of patients experiencing a decrease in PSA by 50%. Secondary endpoints were PSA progression-free survival and adverse events.

The study design is shown below. In total 98 patients were treated with LuPSMA and 85 patients were treated with cabazitaxel.

The study met its primary endpoint of demonstrating improved rates of 50% reduction in PSA relative to cabazitaxel. There was a 29% absolute improvement in this rate, and a 23% improvement after planned sensitivity analysis given patient dropout.

PSA progression-free survival data have not met criteria to reject the null hypothesis as of this presentation. The most common side-effects from LuPSMA therapy were thrombocytopenia, dry eyes and dry mouth. The most common Grade 3 or 4 toxicity was thrombocytopenia.

Dr. Wise suggested that this is a promising therapeutic modality that requires additional data including the quality of life, radiographic progression-free survival and overall survival results from this study, as well as results of the phase III VISION trial comparing LuPSMA to standard of care.

Abstract 5501 – Impact of PSMA-targeted imaging with 18F-DCFPyL-PET/CT on clinical management of patients (pts) with biochemically recurrent (BCR) prostate cancer (PCa): Results from a phase III, prospective, multicenter study (CONDOR)

18F-DCFPyL is a PSMA-targeting PET radiopharmaceutical under development for prostate cancer imaging. It is a lysine-linked, urea-based small molecule that is specific for prostate cancer cells. The agent is administered as a bolus injection, then PET imaging is performed 1-2 hours after administration.

In this abstract, the authors presented data from the CONDOR trial, a prospective study designed with the FDA to demonstrate the diagnostic performance of this imaging modality in the context of rising PSA after definitive therapy for localized disease where other imaging modalities fail to identify sites of disease recurrence. The primary endpoint is defined as lower 95% confidence interval of the correct localization rate > 20%. The correct localization rate (CLR) is essentially the positive predictive value for identifying a recurrence site. Imaging findings were compared to a composite standard of truth based on either evaluable histopathology, conventional imaging or confirmed PSA response after radiotherapy targeting the presumed site of recurrence. The secondary endpoint was the rate of change in treatment plans based on this imaging modality.

Importantly for this study, the median PSA value was 0.8 (range 0.17-98.45). 68.8% of patients had PSA < 2.0 ng/mL, and 14.9% of patients had PSA >= 5.0.

With regards to the primary endpoint, the study met its goal with all three independent radiology evaluators have a composite localization rate of >85%

64% of evaluated subjects had a change in therapeutic management after 18F-DCFPyL scan. Only 3 patients had an adverse safety event, with 1 out of 208 patients experiencing a hypersensitivity reaction.

Dr. Wise concluded that based on this data, (1) 18F-DFCPyL is more sensitive for detection of recurrent prostate cancer than current standard imaging agents, (2) it has a positive predictive value approaching 85% or greater, and (3) with further positive investigation of this agent, this imaging modality may be a highly accurate diagnostic agent for biochemically recurrent prostate cancer.

Abstract 5602 – HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer

Data suggest that cardiovascular mortality is the leading cause of death in patients who have been diagnosed with prostate cancer. This has been attributed in part to cardiovascular side effects from androgen deprivation therapy (ADT). There are two major mechanisms of ADT, designed to decrease serum testosterone to < 50 ng/dL and starve prostate cancer cells of the fuel necessary for growth. LHRH receptor agonists (leuprolide) provide constitutive stimulation and subsequent downregulation of GnRH receptors in the anterior pituitary gland. GnRH receptor antagonists directly block the function of these receptors in the pituitary. LHRH agonists are associated with a flare increase in FSH/LH production and subsequent testosterone levels such that they can cause a clinical flare. This necessitates the concomitant administration of androgen-receptor antagonists with therapy. GnRH antagonists do not have a flare phenomenon and may have an improved cardiovascular safety profile, but must be administered more frequently.

Regulolix is an oral GnRH antagonist administered daily. In this trial, the authors compared regulolix versus a three-month depot injection of the LHRH agonist leuprolide acetate in men with advanced prostate cancer. The primary endpoint of this study was to compare the number of patients with sustained castrate levels of testosterone after 48 weeks of therapy. The study design is shown below.

This study met its primary endpoint of non-inferiority of regulolix compared to leuprolide for sustained castration. 

Importantly, patients who came off treatment with either agent had a quicker recovery of testosterone levels if treated with regulolix.

Finally, in an analysis of cardiovascular events, overall rates were higher in the leuprolide group relative to the regulolix group, especially in patients with a prior history of non-fatal myocardial infarction or non-fatal stroke.

Dr. Wise concluded that regulolix is an effective mechanism of inducing testosterone suppression and may be beneficial for patients who have a significant history of cardiovascular disease. He intends to use this drug for patients without GI absorption issues and with significant cardiovascular disease history. This will likely require more frequent testosterone checks as the medication is taken orally daily, increasing the risk of medication noncompliance.

Presented by: David R. Wise, MD, PhD, Assistant Professor of Medicine and Urology, Perlmutter Cancer Center and NYU Langone Health, New York, New York

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020. 

(UroToday.com) Intermediate and high-risk localized prostate cancers can be treated with surgery or the combination of radiotherapy and hormonal therapy. The optimal timing of hormonal therapy in relation to radiotherapy for localized prostate cancer is an area of active study. In this poster, Daniel E Spratt, MD, and colleagues pool data from prostate-only radiation in the RTOG9413 trial and data from a phase 3 trial of neoadjuvant versus adjuvant hormonal therapy relative to radiation therapy to further explore the optimal timing of hormonal therapy with prostate-only radiotherapy.

In RTOG9413, patients who received prostate-only radiation were randomized to either androgen-deprivation therapy (ADT) for two months prior (neoadjuvant) to the start of radiation therapy, or ADT starting after radiation (adjuvant) and continuing for four months. Patients on this trial who received prostate-only radiation and adjuvant hormonal therapy had numerically higher progression-free survival than patients getting neoadjuvant hormonal therapy. In the other phase 3 trial published by Malone et al of patients undergoing prostate-only radiotherapy, patients were randomized to ADT starting 4 months before radiation (neoadjuvant), or ADT starting with radiation therapy and continuing for 6 months after (adjuvant). The Malone study did not detect any difference in biochemical recurrence rates, overall survival, or late toxicities between either group.

In their pooled analysis, patients from both trials and either neoadjuvant or adjuvant hormonal therapy were combined. This combination gave a cohort of 531 neoadjuvant treated patients, and 534 adjuvantly treated patients. Baseline characteristics were well-balanced between arms. The authors examined the relationship between hormonal therapy timing and various parameters including biochemical failure, progression-free survival, distant metastasis, overall survival and prostate cancer-specific mortality.

The results from this poster show statistically superior rates of biochemical failure (15yr: 33% vs 43%, HR: 1.37 (95%CI: 1.12-1.68), p=0.002), distant metastasis  (15yr: 12% vs 18%, HR: 1.40 (95%CI: 1.00-1.95), p=0.04),  and progression-free survival (15yr: 36% vs 29%, HR: 1.25 (95%CI: 1.07-1.47), p=0.01) with adjuvant hormonal therapy. While numerically better, there was no statistically significant difference in prostate cancer-specific mortality between the arms (15yr: 15% vs 20%, HR: 1.29 (95%CI: 0.95-1.75), p=0.10). There was also no difference in late toxicities between either method.

From this posthoc analysis, the authors suggest that adjuvant hormonal therapy may be preferable to neoadjuvant hormonal therapy when given with prostate-only radiation for the management of localized cancer.

Presented by: Daniel E Spratt, MD, Associate Professor and Chair of Genitourinary Clinical Research, Rogel Cancer Center, University of Michigan, Ann Arbor, MI

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020. 

(UroToday.com) In this presentation, Elizabeth Plimack, MD, discussed the findings from LBA1, a phase 3 randomized study of maintenance avelumab in advanced urothelial cancer patients who have not progressed with first-line platinum-based chemotherapy.

(UroToday.com) Advanced urothelial carcinoma resulted in over 200,000 deaths across the world in 2018. Though the majority of patients eligible for such therapy respond to platinum-based chemotherapy, disease progression occurs relatively quickly and a half or less of patients receive second-line treatment. Though PD-L1/PD-1 immune checkpoint blockade (ICB) agents are standard 2^nd-line therapy for disease progression after platinum, not all patients receive this therapy and only a minority of patients have a durable clinical benefit. Avelumab, an antibody against PD-L1, is approved in the second-line post-platinum treatment setting.

(UroToday.com) There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients. These agents, as well as darolutamide, were subsequently approved on the basis of demonstrated improvements in metastasis-free survival. While metastasis-free survival has been shown to be a reasonable surrogate for overall survival in this population, there were questions as to whether the benefit of using androgen-axis inhibitors would translate to overall survival benefits, in part due to the differential survival effect seen according to disease burden in CHAARTED. While overall survival data from SPARTAN have been previously reported, Karim Fizazi, MD, PhD, and colleagues present the overall survival data assessing darolutamide in non-metastatic castration-resistant prostate cancer from ARAMIS in the Poster Discussion section of the 2020 American Society of Clinical Oncology Virtual Annual Meeting.

As a brief reminder, darolutamide is an androgen receptor inhibitor with a structure distinct from apalutamide and enzalutamide. Perhaps as a result of this structural difference, indirect comparisons from network meta-analysis have shown it to have a favorable safety profile compared to these other agents.

(UroToday.com) Genomic characterization of metastatic castrate-resistant prostate cancer has identified commonly occurring alterations but also recurrently altered genes at much lower frequencies. In this presented poster, the authors aimed to evaluate the anti-tumor activity of novel targeted therapies in patients with metastatic castrate-resistant prostate cancer. For the purpose of this goal, the authors initiated an umbrella trial using circulating tumor DNA (ctDNA) to enrich accrual for cancers with alterations that may predict the response (NCT02905318, NCT03385655).

(UroToday.com) One cycle of adjuvant BEP chemotherapy has shown superiority and a clear benefit in recurrence-free survival over retroperitoneal lymph node dissection (RPLND) in patients with clinical stage 1 non-seminoma germ cell tumors, according to a German randomized phase 3 trial published in the Journal of Clinical oncology back in 2008.¹

In this poster, the authors present updated results of this trial, including recurrences and patient-reported late toxicities after 13 years of follow-up.

The study design is shown in Table 1. Patients in arm A received 1 cycle of BEP chemotherapy, and patients in arm B underwent RPLND surgery.

Table 1- Study design:

All patients answered specific questionnaires about general and specific chemotherapy- and surgery-related items, with all questions being closed-ended questions (multiple choice). The results demonstrated a benefit in progression-free survival in patients treated with BEP chemotherapy but no difference in the overall survival, as can be seen in Figure 1.  Table 2 demonstrates the number of additional recurrences that occurred in this extended follow-up period. Overall, there was only one more single recurrence in each arm during this extended follow-up time. In the original study, there were 15 recurrences in the RPLND arm and only two recurrences in the BEP chemotherapy arm.

Figure 1 – Progression-free and overall survival:

Table 2 – Follow-up and oncological findings:

When assessing patient-reported toxicities, the only significant difference was seen with retrograde ejaculation being more common in the RPLND arm with 24% versus 9%, p=0.01 (Table 3).

Table 3 – Patient-reported toxicities:

The study’s limitations include lack of CTC grading of toxicities, a limited number of patients that were accrued, and the fact that this study was based on patient-reported outcomes with no objective medical data available.

The authors concluded that after 13 years of follow-up, recurrences in clinical-stage one non-seminoma germ cell tumor remains to be significantly more frequent with retroperitoneal lymph node dissection than with BEP chemotherapy. There was no excess mortality due to secondary malignancies in this extended follow-up, and late toxicities were not different between one cycle of BEP and RPLND.

Presented by: Andreas Hiester, Department of Urology, Heinrich-Heine-University, Düsseldorf, Germany

Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, Twitter: @GoldbergHanan, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020. 

References:

1. Albers P, Siener R, Krege S, et al. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2008; 26(18): 2966-72.