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Key Studies in Genitourinary Cancers: Independent Conference Coverage of the 2020 ASCO Virtual Scientific Meeting

Daniel P. Petrylak, MD
Elizabeth R. Plimack, MD, MS
Released: September 1, 2020

Prostate Cancer

COSMIC-021 Cohort 6: Cabozantinib Plus Atezolizumab in Metastatic Castration-Resistant Prostate Cancer

Daniel P. Petrylak, MD:
COSMIC-021 is a phase Ib study of cabozantinib and atezolizumab in advanced solid tumors. At the ASCO 2020 meeting, data from various solid tumors were presented, including in prostate cancer, UC (Capsule Summary), and lung cancer.[30-32] Here, we will discuss the data from the dose-expansion stage of cohort 6, which included men with metastatic CRPC.[30] Individually, these 2 agents have failed miserably in prostate cancer,[33,34] so it is surprising that COSMIC-021 reported positive results.

Patients were eligible for cohort 6 of COSMIC-021 if they had metastatic CRPC with evidence of progression after enzalutamide and/or abiraterone, an ECOG PS of 0/1, and no previous chemotherapy except docetaxel for metastatic CRPC. Patients received cabozantinib 40 mg daily PO plus atezolizumab 1200 mg every 3 weeks by IV. The primary endpoint was ORR as assessed by the investigator, per RECIST v1.1 criteria. Forty-four patients were included in this analysis, and the median follow-up was 15.8 months (range: 9-23).

COSMIC-021 Cohort 6: Efficacy of Cabozantinib Plus Atezolizumab in Metastatic CRPC

Daniel P. Petrylak, MD:
The investigator-assessed ORR was 32% (80% CI: 23% to 42%), which is unheard of in CRPC with either of these agents as a monotherapy. It was 33% in 36 patients with visceral and/or extra-pelvic lymph node metastases. Some patients experienced an increase in tumor volume before responding, which supports the concept that cabozantinib encourages trafficking of certain T-cell populations into the tumor milieu, increasing the presence of T cells that may be involved in immune response, and perhaps removing regulatory T-cells, thereby synergizing the effect of the ICI.[35]

The median DoR was 8.3 months and the median duration of exposure was 6.9 months. Grade 3/4 TRAEs occurred in 59%, grade 3/4 IRAEs in 9.1%, and grade 5 TRAEs in 2.3% of patients.

Elizabeth R. Plimack, MD, MS:
We began our discussion with the KEYNOTE-426 study of a VEGF TKI and IO combination,[1] and we are enrolling for COSMIC-021 Renal at Fox Chase as well. Maybe atezolizumab augmented the response to the VEGF inhibitor here. This trial is small, but these findings are hypothesis generating, and certainly encourage enthusiasm to enroll patients into a larger trial.

Daniel P. Petrylak, MD:
We have not seen a great deal of data on ICIs in prostate cancer. We have recently seen data from a phase II study of pembrolizumab monotherapy in treatment-resistant metastatic CRPC showing limited activity,[36] and another small dataset has been reported.[37] We are excited about the combination of cabozantinib and atezolizumab and look forward to seeing more data. 

ARAMIS: Study Design

Daniel P. Petrylak, MD:
Until 2018, there was no FDA-approved treatment for patients who had a rising prostate-specific antigen (PSA) and nonmetastatic CRPC. There were 3 randomized phase III trials comparing an antiandrogen of choice (darolutamide, apalutamide, or enzalutamide) vs placebo in patients with nonmetastatic CRPC, and each have led to FDA approval of these drugs for use in this setting.[38-40]

Darolutamide was evaluated in nonmetastatic CRPC in ARAMIS, a randomized, double-blind phase III trial conducted in 1509 patients with PSA doubling time ≤ 10 months, and PSA ≥ 2 ng/mL.[38] The primary endpoint of metastasis-free survival was met at the primary analysis, at which point, the median metastasis-free survival was 41.4 months with darolutamide vs 18.4 months with placebo (HR: 0.41; 95% CI: 0.34-0.50; P < .0001). Longer-term follow-up from the final analysis of ARAMIS were reported at the ASCO 2020 meeting (Capsule Summary).[41]

 

ARAMIS: OS With Darolutamide Plus ADT vs Placebo Plus ADT in Nonmetastatic CRPC

Daniel P. Petrylak, MD:
After a median follow-up of 29.1 months, the 36‑month estimated OS was 83% for darolutamide vs 77% for placebo: HR: 0.69 (95% CI: 0.53-0.88; P = .003).[41] This compares with HRs of 0.73 (95% CI: 0.61-0.89; P = .001) for OS in the final analysis of the phase III enzalutamide trial,[42] and 0.75 (95% CI: 0.59-0.96; P = .0197) in the second interim analysis of the apalutamide trial.[39] This suggests that outcomes are similar to use of apalutamide, enzalutamide, or darolutamide in this population.

ARAMIS: Secondary Clinical Endpoints

Daniel P. Petrylak, MD:
The secondary endpoints of time to pain progression (HR: 0.65; 95% CI: 0.53-0.79; P < .001), time to first cytotoxic chemotherapy (HR: 0.58; 95% CI: 0.44-0.76; P < .001), and time to first symptomatic skeletal event (HR: 0.48; 95% CI: 0.29-0.82; P = .005) were all significantly longer with darolutamide.[41]

ARAMIS: Final Safety Analysis (Double Blind)

Daniel P. Petrylak, MD:
In the final analysis of ARAMIS, the safety of darolutamide was in line with the findings of the primary analysis.[41] Grade 3/4 AEs occurred in 26.3% of patients receiving darolutamide vs 21.7% of those receiving placebo. AEs that we would expect with antiandrogens, such as fatigue, fractures, falls, and asthenic conditions, occurred at a similar or slightly higher frequency with darolutamide than with placebo. The rate of seizures with darolutamide was 0.2%, which was similar to placebo.

Safety Comparison of Androgen Receptor Antagonists

Daniel P. Petrylak, MD:
The important question is whether there is a difference in the safety of darolutamide compared with apalutamide and enzalutamide. An analysis of data from the placebo-controlled phase III trials of these agents was presented at the ASCO 2020 meeting.[43]

Overall, there were no statistically significant differences in general safety outcomes between the different agents. Darolutamide was associated with a significantly lower absolute risk of some AEs. Compared with apalutamide, falls (-6% difference in risk differences), rash (-16%), and fractures (-6%) were reduced with darolutamide. When comparing darolutamide with enzalutamide, falls (-6%), dizziness (-5%), mental impairment disorder (-4%), hypertension (-4%), fatigue (1-3%), and severe fatigue (-2%) were reduced with darolutamide.

We know that the penetration of darolutamide into the central nervous system is lower than the other 2 agents, which may explain some of these differences in safety outcomes.[44] It is not clear whether the difference in the frequency of falls is related to central nervous system penetration or to the loss of muscle mass, which we know occurs with antiandrogens. A randomized phase II trial comparing the effects of darolutamide vs enzalutamide on cognitive function will hopefully begin recruiting in 2020,[45] and will provide important data on this question.

In addition, fewer patients in the ARAMIS study of darolutamide were receiving bone-sparing agents than in the SPARTAN study of apalutamide, or the PROSPER study of enzalutamide, which may also reflect differences in bone health between participants at baseline.

ARV-110 in Prostate Cancer: Study Design

Daniel P. Petrylak, MD:
ARV‑110 is a unique drug called a proteolysis-targeting chimera (or PROTAC), which is a protein degrader that helps the E3 ubiquitin ligase bind to a disease-targeted protein and enter the proteasome for degradation.[46] ARV-110 has a protein ligand domain that targets wildtype and altered AR proteins along with a linker region and ligase ligand to orient the structure for degradation and recruit the E3 ubiquitin ligase for protein degradation. PROTACs are recycled during the degradation process and as many as 200 targeted proteins can be destroyed using a PROTAC. ARV-110 can degrade ≥ 90% of AR protein in model systems, and has been designed to target specific AR mutations. In preclinical studies, ARV-110 degraded many common mutant AR forms (T878A, H875Y, F877L, M895V) but not L702H or AR-V7.

Initial results from a first-in-human, dose-escalation phase I trial of ARV-110 in 22 patients with CRPC were reported at the ASCO 2020 meeting (Capsule Summary). Participants were required to have received ≥ 2 previous systemic therapies including abiraterone or enzalutamide, and to have progressed on their most recent therapy. The trial was designed to define the maximal tolerated dose and a recommended phase II dose, as well as assess pharmacokinetics and tumor activity, and explore the impact on biomarkers.

ARV-110 in Prostate Cancer: Baseline Characteristics

Daniel P. Petrylak, MD:
At baseline, 68% of patients had an ECOG PS of 0. The median number of previous regimens in metastatic CRPC was 5.[46] All patients had previously received abiraterone, 77% had received enzalutamide, or both abiraterone and enzalutamide, and 77% had received previous chemotherapy. Other agents, such as lutetium (9%), radium 223 (23%), sipuleucel‑T (23%), and PARP inhibitors (23%), had also been administered to these patients.

ARV-110 in Prostate Cancer: Adverse Events

Daniel P. Petrylak, MD:
TRAEs occurred in 59% of patients overall and were generally mild except for 2 patients with transaminitis of grade 3/4 severity that were linked to rosuvastatin use.[46] One patient with a grade 3 transaminitis event stopped rosuvastatin treatment and ARV‑110, and did not develop grade 3 transaminitis after rechallenge with ARV-110 without rosuvastatin. 

ARV-110 in Prostate Cancer: Safety and Pharmacokinetics

Daniel P. Petrylak, MD:
When assessing the levels of rosuvastatin in these patients, there was a 7-14 times increase in rosuvastatin compared with baseline due to inhibition of the BCRP transporter by ARV-110. Based on these data, the use of rosuvastatin was restricted in any further patients receiving ARV-110.[46]

There was no transaminitis in patients receiving other statins.

Plasma exposure was dose proportional at all doses of ARV-110 used, and doses ≥ 140 mg daily produced exposures that were associated with tumor growth inhibition in the preclinical models.

ARV-110 in Prostate Cancer: Duration of Therapy

Daniel P. Petrylak, MD:
Data are not yet mature for the duration of therapy and one half of the patients are still on treatment..[46] For the patients receiving 280 mg ARV-110, most had received 5 weeks of therapy at the time of data analysis, so longer follow-up is needed.

ARV-110 in Prostate Cancer: Activity

Daniel P. Petrylak, MD:
Among 20 evaluable patients, 1 had a confirmed RECIST response and 2 had confirmed PSA responses of greater than 50%, both with the 140 mg dose.[46] Both responding patients had the same AR mutations, T878A and H875Y, and had failed abiraterone and enzalutamide. Both of these mutations have been associated with resistance to abiraterone and enzalutamide.

One patient had a T878A mutation and an ARV7 mutation. We do not know whether ARV7 is an epiphenomenon or whether it truly is a resistance mutation, but ARV7 is not targeted by the PROTAC.

Overall, these data show that there is a clear response with ARV-110, and that is pretty exciting.

ARV-110 in Prostate Cancer: Activity of ≥ 140 mg Dose by AR Biomarker Status

Daniel P. Petrylak, MD:
When the analysis was restricted to  patients who received a dose ≥ 140 mg, 2 of 7 patients without AR-V7 or L702H, which are both mutations not targeted by ARV-110, responded by PSA reduction and/or by RECIST.[46]

ARV-110 in Prostate Cancer: Conclusions

Daniel P. Petrylak, MD:
These data are very much preliminary, but they do provide evidence of a response to a first-in-class, first-in-human agent, which, I think, is pretty exciting.

Elizabeth R. Plimack, MD, MS:
I certainly hope ARV-110 proves to be a beneficial agent for our patients, but clearly, these are very early data. I think every clinical trial I have ever been involved with has had 1 or 2 patients who do really well, regardless of the others, and this one is probably no exception, so I am waiting to see more data.

Daniel P. Petrylak, MD:
The data are clearly not practice changing, but I think this trial is an interesting start. If the PROTAC mechanism has some durable activity, it would expand our therapeutic milieu to areas that may be not targetable with current drugs. There is a similar trial that is being conducted in breast cancer with the estrogen receptor, so those data are going to be interesting to see.[47]

Summary

Daniel P. Petrylak, MD:
This was an exciting year at ASCO for our patients with genitourinary malignancies. In RCC, the KEYNOTE-426 data gave us important insights with longer follow-up for the use of an IO/TKI combination approach as first-lien therapy. In bladder cancer, the data from the JAVELIN Bladder 100 trial led to rapid FDA approval of avelumab as maintenance therapy for patients in response after platinum-based chemotherapy, and the phase I/II EV-103 data highlighted a potential new IO combination with enfortumab vedotin. In prostate cancer, ARAMIS confirmed the positive data on darolutamide and the use of AR antagonists for patients with CRPC.

There were also various novel treatment approaches presented with the ARV-110 data as well as others, like a phase II trial of lutetium-177 vs cabazitaxel in metastatic CRPC.[48] The PSA response rate favored the prostate-specific membrane antigen (PSMA), lutetium-177; 66% vs 37% with cabazitaxel in this trial.

This is just a sample of the data from ASCO 2020 virtual meeting. More information on other malignancies are also available on the CCO website, including downloadable slideset summaries of all of the key studies from ASCO 2020.

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Supported by educational grants from
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Bristol-Myers Squibb
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