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Key Studies in Genitourinary, Gastrointestinal, Breast, and Lung Cancers: CCO Independent Conference Highlights of the 2021 Virtual ESMO Annual Meeting
  • CME

Eva M. Ciruelos, MD, PhD
Karim Fizazi, MD, PhD
Eric Van Cutsem, MD, PhD
person default
Vamsidhar Velcheti, MD
Released: December 15, 2021

Studies in Genitourinary Cancers from ESMO 2021

VISION: 177Lu-PSMA-617 in Previously Treated Metastatic Castration-Resistant Prostate Cancer

Karim Fizazi, MD, PhD:
I would like to start with a study in advanced prostate cancer (PC). The phase III VISION trial is the first trial to focus on 177Lu-PSMA-617, an investigational prostate-specific membrane antigen–targeted radioligand therapy, in men with mCRPC. Results from the VISION trial results were recently published.1 At ESMO 2021, data regarding the health-related quality of life (HRQoL), pain, and safety outcomes with 177Lu-PSMA-617 were presented.2

VISION: Study Design

Karim Fizazi, MD, PhD:
VISION is a randomized, open-label phase III trial of 831 patients with prostate-specific membrane antigen–positive mCRPC previously treated with at least 1 androgen receptor pathway inhibitor, 1 or 2 taxane-base regimens and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Participants were randomly assigned to receive SoC alone or in combination with 177Lu-PSMA-617 every 6 weeks for 4-6 cycles. Approximately 97% of the participants had previously received docetaxel and approximately 40% had previously received cabazitaxel.

Alternate primary endpoints were radiographic PFS and OS; secondary endpoints included safety, tolerability, PSA level, HRQoL, and pain outcomes.

VISION: Survival and Secondary Outcomes

Karim Fizazi, MD, PhD:
The median radiographic PFS in the analysis set was significantly longer with the addition of 177Lu-PSMA-617 to SoC: 8.7 months vs 3.4 months (HR: 0.40; 95% CI: 0.29-0.57; P <.001). The median time to worsening of the Functional Assessment of Cancer Therapy-Prostate total score was significantly improved with the addition of 177Lu-PSMA-617 to SoC and this improvement was clinically meaningful: 9.7 months vs 2.4 months (HR: 0.46; 95% CI: 0.35-0.61; P <.001).

An improvement was clearly also seen in the 177Lu-PSMA-617 arm in terms of the median to worsening of pain intensity using the Brief Pain Inventory-Short Form questionnaire: 14.3 months vs 2.9 months (HR: 0.45; 95% CI: 0.33-0.60; P <.001).

The median time to first symptomatic skeletal events, including mostly fractures, spinal cord compression and major pain requiring radiation, was significantly prolonged with the addition of 177Lu-PSMA-617 to SoC: 11.5 months vs 6.8 months (HR: 0.50; 95% CI: 0.40-0.62; P <.001).

Also, the median OS was significantly improved with the addition of 177Lu-PSMA-617 to SoC, with a 38% reduction in the risk of death: 15.3 months vs 11.3 months (HR: 0.62; 95% CI: 0.52-0.74; P <.001).

VISION: Safety

Karim Fizazi, MD, PhD:
Overall, 177Lu-PSMA-617 is well-tolerated. However, caution is required regarding the associated bone marrow suppression, especially in men with massive bone involvement. Nausea and vomiting are adverse events (AEs) of 177Lu-PSMA-617 that can and should be prevented. Dry mouth is also seen in excess with 177Lu-PSMA-617, but usually this AE is of grade 1/2 intensity and does not seem to last very long in patients. In general, 177Lu-PSMA-617 is a treatment that can be used even in older patients, for instance.

VISION: Conclusions

Karim Fizazi, MD, PhD:
In conclusion, the use of 177Lu-PSMA-617 in combination with SoC for patients with mCRPC who have previously received androgen receptor pathway inhibitors and taxane-based CT extends duration of life, prevents radiographic progression, and delays the time to worsening of HRQoL, delays time to worsening of pain and delays time to first symptomatic skeletal events, such as fractures.

It is becoming clearer that 177Lu-PSMA-617 is an effective agent having been granted Priority Review by the FDA for patients with mCRPC.

PEACE-1: Background

Karim Fizazi, MD, PhD:
The first results from the phase III PEACE‑1 trial for men with metastatic castratation-sensitive PC (mCSPC) were presented at ASCO 2021, where the radiographic PFS results were presented.3 At ESMO 2021, the most important outcome of the trial, OS, was presented.4

In the past 5-6 years, intensification is required for the treatment of men with metastatic PC; this is backed with level 1 evidence. By this, I am referring to the addition of docetaxel, a novel hormonal agent or local radiation therapy to androgen-deprivation therapy (ADT), at least for men with oligometastatic PC. Before the PEACE‑1 trial it was not known which treatments including abiraterone and radiotherapy to combine with SoC for men with de novo mCSPC.

PEACE-1: Study Design

Karim Fizazi, MD, PhD:
PEACE-1 was a multicenter, randomized, open-label phase III trial of 1173 patients with mCSPC with distant metastasis by 1 or more lesions on a bone scan or CT scan and an ECOG PS of 0-2. Patients with metastatic relapse were not included in the trial. Patients were stratified based on ECOG PS status, metastatic site, type of castration and prior docetaxel use. Participants were randomly assigned to receive SoC alone, SoC plus radiotherapy, SoC plus abiraterone, or SoC plus both abiraterone and radiotherapy. A 2x2 factorial design was used to answer 2 questions. First, should abiraterone be combined with ADT and docetaxel, and second, should radiotherapy be used when the systemic treatment is intensified?

PEACE-1: Baseline Characteristics in ADT Plus Docetaxel Population

Karim Fizazi, MD, PhD:
This analysis focuses on the 710 patients who received ADT plus docetaxel in the PEACE-1 trial. Overall, the median age was 66 years, and approximately 70% of the patients has an ECOG PS of 0. Most of the baseline characteristics are classical for this population of patients. For example, approximately 80% of patients had bony disease without visceral metastasis, and approximately 64% of patients had high disease burden.

PEACE-1: Radiologic PFS With Abiraterone in ADT Plus Docetaxel Population (With or Without Radiotherapy)

Karim Fizazi, MD, PhD:
The median radiographic PFS was significantly increased with the addition of abiraterone to ADT and docetaxel (SoC): 4.5 years (95% CI: 3.1-not estimable [NE]) vs 2.0 years (95% CI: 1.8-2.3) (HR: 0.50; 95% CI: 0.40-0.62; P <.0001). Patients in the SoC alone arm experienced progression or death after just 2 years, which was expected for this population of patients. On the other hand, patients on the abiraterone plus SoC arm postponed those events by an additional 2.5 years.

PEACE-1: Radiologic PFS With Abiraterone in ADT Plus Docetaxel (With or Without RXT) Population by Metastatic Burden

Karim Fizazi, MD, PhD:
According to metastatic burden, the addition of abiraterone to SoC significantly prolonged radiographic PFS among patients with high volume disease compared with SoC alone: 4.1 years (95% CI: 2.7-NE) vs 1.6 years (95% CI: 1.4-2.0) (HR: 0.47; 95% CI: 0.36-0.60; P <.0001). Similarly, patients with low‑volume disease benefit from the addition of abiraterone to SoC: NE (95% CI: 3.1-NE) vs 2.7 years (95% CI: 2.7-NE) (HR: 0.58; 95% CI: 0.39-0.87; P = .0006).

PEACE-1: OS in Overall Population and ADT Plus Docetaxel Population

Karim Fizazi, MD, PhD:
Regarding OS, the trial is positive. In the overall population, the median OS with the combination of abiraterone and SoC compared with SoC alone extends survival by a year: 5.7 years (95% CI: 5.1-NE) vs 4.7 years (95% CI: 4.3-5.3) (HR: 0.82; 95% CI: 0.69-0.98; P = .030). Focusing on the population of patients who received abiraterone plus SoC, the OS results are more important and interesting, as it provides new insights. When abiraterone is added to the SoC combination of ADT plus docetaxel with or without radiotherapy vs SoC alone, there is a reduction in the risk of death by 25%: NE (95% CI: 4.5-NE) vs 4.4 years (95% CI: 3.8-4.9) (HR: 0.75; 95% CI: 0.59-0.95; P = .017). In this subpopulation of patients, the median OS has not yet been reached in the experimental arm, indicating that the addition of abiraterone to SoC will yield much better results.

PEACE-1: OS by Subgroup With Abiraterone in ADT Plus Docetaxel Population (With or Without Radiotherapy)

Karim Fizazi, MD, PhD:
In the subgroup analysis of OS, generally patients tend to benefit from the addition of abiraterone to SoC regardless of the individual characteristic. The interaction tests were negative. Among patients with a high metastatic burden, abiraterone plus SoC improved OS (HR: 0.72; 95% CI: 0.55-0.95). In the population of men with low metastatic burden, the addition of abiraterone to SoC improved OS (HR: 0.83; 95% CI: 0.50-1.38). Even with a focus on high-volume vs low- volume disease, an important factor for physicians, the addition of abiraterone to SoC prolonged OS. So, when comparing sick men to men with a much longer time before the risk of death from the disease, OS becomes predominant.

PEACE-1: OS with Abiraterone in ADT Plus Docetaxel Population (With or Without Radiotherapy) by Metastatic Burden

Karim Fizazi, MD, PhD:
There is a very clear benefit in the median OS with the addition of abiraterone to ADT plus docetaxel (SoC) among patients with high-volume disease: 5.1 years (95% CI: 3.8-NE) vs 3.5 years (95% CI: 3.2-4.0) (HR: 0.72; 95% CI: 0.55-0.95; P = .019). This is clearly clinically meaningful.

For the population of patients with low-volume disease, it is not as clear. Most men were alive when the analysis was conducted. Of course, this is very good for patients. However, we will need a longer follow-up to figure out whether adding a third drug to ADT and docetaxel improves OS outcomes in patients with low-volume disease. Overall, disease progression is significantly postponed with the 3-drug combination instead of 2 drugs in these men.

PEACE-1: Treatments Beyond Progression in ADT Plus Docetaxel Population

Karim Fizazi, MD, PhD:
Of importance, 81% of patients who received SoC alone (control arm) had access to salvage therapy with a next-generation hormonal agent upon disease progression to CRPC, which is unique. In many trials conducted to date, the percentage is lower resulting in criticisms that patients on the control arm are not sufficiently and aggressively treated after disease progression. Among patients who received SoC alone on the PEACE-1 trial, 84% received at least one life‑prolonging treatment, clearly indicating that early treatment is better than deferred treatment.

PEACE-1: Grade 3-5 Adverse Events Reported in ADT Plus Docetaxel Population

Karim Fizazi, MD, PhD:
It is reassuring that the addition of a third agent to ADT and docetaxel (SoC) does not significantly increase toxicity. No new safety signals were seen in this trial. Toxicities with docetaxel or abiraterone were as expected. In comparison to SoC alone, the addition of abiraterone to SoC was associated with hypertension (22% vs 13%), hypokalemia (3% vs 0), and fatigue (3% vs 4%). Fatigue was experienced by fewer patients on the abiraterone arm than on the control arm. Classical toxicities associated with abiraterone were observed on the PEACE-1 trial.

PEACE-1: Conclusions

Karim Fizazi, MD, PhD:
In conclusion, the addition of abiraterone to ADT/docetaxel was associated with a significant improvement in median radiographic PFS, with a 2.5‑year improvement and of most importance, in OS, with a 25% reduction in the risk of death. Most patients on the control arm had access to salvage therapy, including abiraterone and enzalutamide, upon disease progression to CRPC.

Regarding patients with high‑volume metastases, it is clear that at least in fit men with mCSPC, the triplet regimen is effective and should be considered. For patients with low‑volume disease, the treatment approach may be discussed and debated, given that the OS results are immature. The plan is to reanalyze the trial data in the coming years.

Toxicity was as expected, and this was very reassuring. With this in mind, the recommendation is now to move to the triplet regimen and to discuss its potential advantage, at least with patients with de novo and high‑volume mCSPC who are fit to receive CT.

STAMPEDE: Background

Karim Fizazi, MD, PhD:
Next, we will review the design and results from the STAMPEDE trial.5

There has been no major change regarding the use of systemic treatment in men with high‑risk localized PC in the last 20 years. At that time, it was demonstrated that the use of long‑term ADT in addition to local treatment and radiation improves both PFS and OS.6 Since then, there have been refinements regarding the duration of ADT in this context, and most of the guidelines would support ADT for 18 months to 3 years, probably depending on the risk of the patient.

Docetaxel has been tested in this setting, but the data are debatable. Clearly, docetaxel prolongs relapse‑free survival; this was demonstrated in both the GETUG-12 trial and in prior reports of the STAMPEDE trial.7,8 In these trials, however, metastasis‑free survival (MFS) was not clearly prolonged or improved. As a result, docetaxel is considered in this setting by some physicians, but for many others not.

At ESMO 2021, the important OS and MFS data from the STAMPEDE trial of abiraterone in men with high‑risk, localized PC were reported.5 In my opinion, the STAMPEDE trial results are practice changing.

STAMPEDE Analysis of Abiraterone Plus ADT in High-Risk M0 PCa: Study Design

Karim Fizazi, MD, PhD:
STAMPEDE is a randomized phase III trial of 1974 patients with newly diagnosed or radiotherapy-relapsed, nonmetastatic or high-risk node-negative PC. Participants were randomly assigned to receive SoC alone for 3 years or SoC in combination with abiraterone with or without enzalutamide for 2 years. The trial has a complex design. It is important to remember that STAMPEDE is a never‑ending phase III trial, testing various hypotheses, and asking different questions. One of the important questions being asked is on the efficacy of abiraterone, which has been tested in both the metastatic and nonmetastatic settings. Similar to the LATITUDE trial for newly diagnosed, high-risk mCSPC, which clearly demonstrated that abiraterone plus ADT improves OS compared with ADT alone, STAMPEDE is really specific to men with high‑risk localized disease.5,9 In that regard, STAMPEDE is the only phase III trial looking overall at abiraterone in these men.

In the STAMPEDE trial, high‑risk localized disease was defined as men with at least 2 of the criteria (including T3/4 disease, PSA ≥40 ng/mL, Gleason score of 8-10 disease) or node‑positive disease and/or with a rising PSA level post local treatment.10 The trial included a mixed population of men with PC. As a result, the trial reflects the real practice and knowing the low survival rate in these men, the intention is to try to improve their outcomes.

STAMPEDE Analysis of Abiraterone Plus ADT in High-Risk M0 PCa: Key Baseline and Treatment Characteristics

Karim Fizazi, MD, PhD:
The median age of patients was 68. The median PSA level was 34 ng/mL, and 99% of the patients had newly diagnosed N0 disease. For the analysis, the investigators preplanned to pool together the patients according to the time it took to permanently discontinue treatment with abiraterone (23.7 months), enzalutamide (23.2 months) and abiraterone plus enzalutamide (20.7 months).

STAMPEDE Analysis of Abiraterone Plus ADT in High-Risk M0 PCa: Metastasis-Free Survival

Karim Fizazi, MD, PhD:
In the analysis, MFS was very clearly and significantly improved with the addition of abiraterone to ADT, with a 47% reduction in the risk of metastases or death and a p value that is highly significant. In the overall population, the 6-year MFS significantly improved with the addition of abiraterone to ADT: 82% vs 69% (HR: 0.53; 95% CI: 0.44-0.64; P = 2.9 x 10-11). This was true when abiraterone alone was added to SoC or when abiraterone and enzalutamide were added to SoC. The addition of both abiraterone and enzalutamide to SoC adds some power to detect the difference in MFS, but basically the data are exactly the same.

STAMPEDE Analysis of Abiraterone Plus ADT in High-Risk M0 PCa: Metastasis-Free Survival Subgroup Analyses

Karim Fizazi, MD, PhD:
Overall, there was a trend toward benefit from the addition of abiraterone with or without enzalutamide in terms of MFS. This was true, for example, for both patients with N0 and N‑positive disease and regardless of whether the patients received prostate radiotherapy or not. These results are clinically very important.

STAMPEDE Analysis of Abiraterone Plus ADT in High-Risk M0 PCa: Overall Survival

Karim Fizazi, MD, PhD:
For the first time in approximately 20 years, we have OS data with abiraterone in combination with ADT in the STAMPEDE trial for men with high‑risk localized PC, and the news is good. In the overall population, the addition of abiraterone with or without enzalutamide to ADT resulted in a 40% reduction in the risk of death. In the overall population, the 6-year OS rate was significantly improved with the addition of abiraterone: 86% vs 77% (HR: 0.60; 95% CI: 0.48-0.73; P = 9.3 x 10-7). This difference is very highly significant, and this benefit was achieved regardless of whether enzalutamide was combined with abiraterone or not.

STAMPEDE Analysis of Abiraterone Plus ADT in High-Risk M0 PCa: Other Secondary Outcomes

Karim Fizazi, MD, PhD:
The analysis of other secondary outcomes showed a significant improvement in the 6-year PC-specific survival with the addition of abiraterone with or without enzalutamide to ADT compared with ADT alone: 93% vs 85% (HR: 0.49; 95% CI: 0.37-0.65; P = 1.3 x 10-6). As expected, the PFS was also significantly improved with the addition of abiraterone with or without enzalutamide to ADT (P = 5.2 x 10-15).

STAMPEDE Analysis of Abiraterone Plus ADT in High-Risk M0 PCa: Adverse Events

Karim Fizazi, MD, PhD:
Abiraterone added only modest additional toxicity to SoC in men with high-risk M0 PC. It is important to remember that in the STAMPEDE trial abiraterone was administered for only 2 years.

STAMPEDE Analysis of Abiraterone Plus ADT in High-Risk M0 PCa: Conclusions

Karim Fizazi, MD, PhD:
In conclusion, the key takeaway from the STAMPEDE trial is that adding 2 years of abiraterone to ADT for men with high‑risk nonmetastatic PC clearly improves MFS and OS. In my opinion, this combination should immediately become a new SoC for these men. Unfortunately, abiraterone is not yet FDA approved for men with high-risk, nonmetastatic PC. However, the difference is significant enough that we should do our best to use this drug in this setting, especially since abiraterone is already a generic drug in most countries worldwide and since it is going to become generic in Europe next year.

COSMIC-021 mCRPC Cohort: Background

Karim Fizazi, MD, PhD:
At ESMO 2021, data from the COSMIC-021 trial of cabozantinib in combination with atezolizumab for men with mCRPC were reported.11 Cabozantinib inhibits multiple receptor tyrosine kinases. It is known to improve bone pain from mCRPC. In the randomized phase III COMET-1 trial of cabozantinib vs prednisone for patients with previously treated mCRPC, cabozantinib significantly improved bone scan response and radiographic PFS.12 Unfortunately, in that trial, OS was not significantly improved compared with prednisone. This is why cabozantinib is currently does not have FDA approval for patients with mCRPC.

The investigators combined cabozantinib with atezolizumab based on the rationale that cabozantinib has the potential to encourage an immune‑permissive microenvironment that could enhance the effect of immune checkpoint inhibitors.13 In addition, the DoR to cabozantinib is relatively short in men with mCRPC.12 The hope is that combining cabozantinib with an immune-checkpoint inhibitor would prolong response.

COSMIC-021 Expanded mCRPC Cohort: Study Design

Karim Fizazi, MD, PhD:
COSMIC-021 is a multicenter, multicohort phase Ib trial of 132 patients with mCRPC and radiographic progression in soft tissue after enzalutamide and/or abiraterone therapy. Participants received oral cabozantinib at a dose of 40 mg once daily, and atezolizumab was administered intravenously at 1200 mg every 3 weeks. The study included 1 initial cohort of patients and 2 extended enrollment cohorts, which were added to the initial cohort of patients. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and the secondary endpoints included safety and exploratory endpoints of PFS, OS and biomarker analyses.

We already have preliminary data from the initial cohort of patients on the COSMIC-021 trial with the combination, showing some encouraging clinical activity.14 The data presented at ESMO 2021 were for the expanded cohort of patients with mCRPC.

COSMIC-021 mCRPC Cohort: Baseline Characteristics

Karim Fizazi, MD, PhD:
As expected, the baseline characteristics of the population were typical for patients with mCRPC. The median age was 70, 52% of the patients had an ECOG PS of 0 and 48% had an ECOG PS of 1. Most participants had bone metastases (54%), 19% had lung metastasis, and 13% had liver metastasis. The median follow-up at the time of data analysis was 15.2 months (range: 5.7-33.9).

COSMIC-021 mCRPC Cohort: Response by RECIST v1.1

Karim Fizazi, MD, PhD:
In the overall population, the investigator-assessed ORR by RECIST v1.1 was 23%. When the analysis was restricted to patients with visceral disease or extrapelvic lymphadenopathy (EPLN), the ORR was 27%. Of concern, lymph node disease was pooled together with visceral disease, and both are not of the same prognosis. The ORR by the BIRC was much lower at 15% in the overall population and 18% in patients with visceral disease or EPLN.

COSMIC-021 mCRPC Cohort: PFS

Karim Fizazi, MD, PhD:
In the overall population, the median PFS was 5.5 months (95% CI: 4.3-6.6) by investigator assessment, and 5.7 months (95% CI: 5.4-7.0) by BIRC. In the population of patients with visceral disease or EPLN, the median PFS was 5.6 months (95% CI: 5.4-8.2) by investigator assessment and 6.8 months (95% CI: 5.5-9.7) by BIRC. These results suggest that the median PFS ranges from approximately 5 to 6 months, regardless of who looks at the data and regardless of the population selected.

COSMIC-021 mCRPC Cohort: OS

Karim Fizazi, MD, PhD:
The median OS was 18.4 months in the overall population and in the population of patients with visceral disease or EPLN.

COSMIC-021 mCRPC Cohort: PSA Change From Baseline

Karim Fizazi, MD, PhD:
The PSA response shows that 54% of men benefit with treatment. However, only 26% of patients achieved a decrease in PSA by 50% or more. This was perhaps lower than expected.

COSMIC-021 mCRPC Cohort: Safety Overview and Adverse Events of Special Interest

Karim Fizazi, MD, PhD:
The safety results are as expected. Both cabozantinib and atezolizumab can have some toxicity in patients. Cabozantinib used at 40 mg seems to be better tolerated than when reported in the phase III COMET-1 trial, when it was administered at the 60-mg dose.12 Also, atezolizumab adds some immune-related toxicities, including hyperthyroidism and hepatitis.

COSMIC-021 mCRPC Cohort: Conclusions

Karim Fizazi, MD, PhD:
In conclusion, the combination of cabozantinib with atezolizumab demonstrated anticancer activity. It is not clear whether this activity is truly encouraging with a 23% ORR by investigator assessment (15% ORR by BIRC) and a relatively short DoR of 6.9 months. The phase III CONTACT-02 trial is currently enrolling, but of concern is whether the data from the COSMIC-021 trial are sufficient to justify a phase III trial.15 However, I hope that the phase III trial will provide a positive finding with regard to OS and radiographic PFS. The exact role of the atezolizumab component in the combination is questionable, and it is unclear whether what was seen in the phase Ib COSMIC-021 trial is simply the efficacy of cabozantinib, as we already know it from previous phase II and phase III trials. Nonetheless, data from longer‑term follow-up studies should provide the answers to some remaining questions.

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