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Key Studies in Urothelial, Prostate, and Kidney Cancer: CCO Independent Conference Highlights of the 2021 Genitourinary Cancers Symposium

Robert Motzer, MD
Daniel P. Petrylak, MD
Released: March 26, 2021

Prostate Cancer

KEYNOTE-365 Cohort B: Pembrolizumab + Docetaxel in Pretreated Patients With mCRPC

Daniel P. Petrylak, MD:
Moving on to prostate cancer, there were 2 phase II trials of interest presented at ASCO GU 2021, both of which led to large, randomized clinical trials. The theory behind these studies is that immunotherapy may potentiate the effect of chemotherapy—inducing cellular damage with chemotherapeutic agents may make cells more responsive to the immune system.

KEYNOTE-365 is an ongoing, multicohort study; cohort B is evaluating pembrolizumab combined with docetaxel/prednisone in patients with pretreated metastatic castration‑resistant prostate cancer.5 The current analysis reports 1 additional year of follow-up for KEYNOTE-365 cohort B.6 Patients either failed or were intolerant of abiraterone or enzalutamide with no prior chemotherapy. The coprimary endpoints were safety, prostate-specific antigen (PSA) response rate, and ORR. Key secondary endpoints were the DCR and radiographic PFS.

KEYNOTE-365 Cohort B: ORR and PSA Response

Daniel P. Petrylak, MD:
Half of the patients had measurable disease with an ORR of 23% and a DCR of 73%. The confirmed PSA response rate, it was 34.0% in all patients, 27.5% in patients with measurable disease, and 40.0% in those with nonmeasurable disease.

KEYNOTE-365 Cohort B: rPFS and OS

Daniel P. Petrylak, MD:
The median radiographic PFS was 8.5 months, and the median OS was approximately 20 months. So, putting this in the context of CRPC, these are patients who progressed after abiraterone or enzalutamide, and one may think that the OS rate might be a little low. In retrospective studies looking at docetaxel after abiraterone, the median OS was somewhat lower at approximately 12.5 months.7 But again, I think these findings here are interesting and led to the phase III KEYNOTE-921 of pembrolizumab plus docetaxel vs placebo plus docetaxel in chemotherapy-naive mCRPC, which is currently ongoing and accruing patients (NCT03834506).

KEYNOTE-365 Cohort B: Safety

Daniel P. Petrylak, MD:
There were 2 treatment‑related deaths due to pneumonitis. It is difficult to determine whether they were from docetaxel or pembrolizumab since pneumonitis is a known AE for both drugs. The median duration on treatment was nearly 8 months.

KEYNOTE-365 Cohort B: Conclusions

Daniel P. Petrylak, MD:
The combination of pembrolizumab with docetaxel and prednisone continues to show promising antitumor activity in previously treated mCRPC after 1 additional year of follow-up.6

CheckMate 9KD Arm B: Nivolumab + Docetaxel in Chemotherapy-Naive mCRPC

Daniel P. Petrylak, MD:
At ASCO GU 2021, Fizazi and colleagues reported results from the multi-arm phase II CheckMate 9KD study evaluating nivolumab in combination with docetaxel in 84 patients with chemotherapy-naive mCRPC who could have received up to 2 prior novel antiandrogen therapies.8 Nivolumab was given at 360 mg along with docetaxel every 3 weeks; patients who completed chemotherapy went on to maintenance nivolumab at 480 mg every 4 weeks. The coprimary endpoints were ORR per investigator and PSA response rate. Key secondary endpoints were radiographic PFS, OS, time to response, DoR, time to PSA progression, and safety.

CheckMate 9KD Arm B: ORR and PSA Response

Daniel P. Petrylak, MD:
The ORR was 40% in all patients, 42.9% in those with no prior novel antiandrogen therapy, and 38.7% in those with prior novel antiandrogen therapy. When we look at the PSA response, the confirmed PSA response rate was 46.9% in all patients and 60.7% in those without prior novel antiandrogen therapy.

CheckMate 9KD Arm B: Maximum Tumor Size Change From Baseline

Daniel P. Petrylak, MD:
The maximum shrinkage in tumor size from baseline was similar in patients with no prior novel antiandrogen therapy and in those with prior novel antiandrogen therapy, with the caveat that the patient numbers were small in this study.

CheckMate 9KD Arm B: Maximum PSA Change From Baseline

Daniel P. Petrylak, MD:
Looking at the maximal change in PSA from baseline, a similar reduction was observed in patients with or without previous novel antiandrogen therapy. Overall, a reduction from baseline in PSA was observed in 68 of 81 evaluable patients (84.0%).

CheckMate 9KD Arm B: Radiographic PFS and OS

Daniel P. Petrylak, MD:
If we look at the 1-year radiographic PFS rate, it was 36% in all patients. In patients who had novel antiandrogen therapy, it was 26%, and in those without prior novel antiandrogen therapy, it was 51%. The 1-year OS rate was 70% in all patients and 69% in those with or without prior novel antiandrogen therapy.

CheckMate 9KD Arm B: Safety

Daniel P. Petrylak, MD:
Grade 3/4 TRAEs led to discontinuation in 14.3% of patients. There was also 1 death due to pneumonitis, which was related to nivolumab, and 2 deaths due to pneumonia that were related to docetaxel, and this is something that needs to be evaluated carefully for this drug combination. 

CheckMate 9KD Arm B: Takeaways

Daniel P. Petrylak, MD:
In CheckMate 9KD arm B, nivolumab with docetaxel and prednisone showed promising antitumor activity in a larger number of patients with chemotherapy-naive mCRPC.8

ICI + Docetaxel in mCRPC: Conclusions

Daniel P. Petrylak, MD:
I think findings from KEYNOTE-365 are interesting, and they led to the phase III KEYNOTE-921 of pembrolizumab plus docetaxel vs placebo plus docetaxel in chemotherapy naive mCRPC, which is currently ongoing and accruing patients (NCT03834506). Also, an important thing to note is that even though the data from the CheckMate 9KD are interesting, randomized trials are needed to determine whether this is a true effect or due to patient selection. Currently, there is also an ongoing phase III trial of docetaxel with or without nivolumab in patients with mCRPC (NCT04100018).

ACIS: Apalutamide + Abiraterone vs Placebo + Abiraterone in Chemotherapy-Naive mCRPC

Daniel P. Petrylak, MD:
Maximum androgen blockade in the frontline setting of mCRPC is something that has been evaluated in clinical trials including a study that looked at abiraterone with or without enzalutamide.9 The phase III ACIS trial, with a similar design, looked at apalutamide combined with abiraterone and prednisone vs placebo plus abiraterone and prednisone in patients with mCRPC who had progressed on androgen deprivation therapy and had not received any prior systemic therapy for CRPC.10 The primary endpoint was investigator-assessed radiographic PFS and secondary endpoints included OS, time to chemotherapy, time to pain progression, and time to chronic opioid use.

ACIS: rPFS (Primary Endpoint)

Daniel P. Petrylak, MD:
With a median follow-up of 25.7 months, there was a 6‑month improvement in median radiographic PFS in favor of the combination with apalutamide plus abiraterone (HR: 0.69; P <.0001), and at a median follow-up of 54.8 months, median radiographic PFS was 24.0 months vs 16.6 months with an HR of 0.70. The radiographic PFS benefit was observed across prespecified subgroups including patients with visceral metastases and who were 75 years of age or older.

ACIS: Other Endpoints

Daniel P. Petrylak, MD:
However, when we look at the secondary endpoint of OS, there was no significant difference between apalutamide combined plus abiraterone and prednisone vs placebo plus abiraterone and prednisone (HR: 0.95; P = .498), which is consistent with what we saw in other studies.9 Although it was disappointing, it was consistent with what had been previously reported.9 There were no significant differences in other secondary and exploratory endpoints as well.

ACIS: PSA Outcomes

Daniel P. Petrylak, MD:
Regarding PSA outcomes, more patients in the combination arm achieved a confirmed decline of ≥50% in PSA level (relative risk: 1.09; P = .015) and undetectable PSA (<0.2 ng/mL) at any time during treatment (relative risk: 1.28; P = .040). Median time to PSA progression was longer in the combination arm at about 13.8 months vs 12.0 months, but this difference was not significant (HR: 0.87; P = .076).

ACIS: Safety

Daniel P. Petrylak, MD:
In regard to safety, the combination regimen led to slightly higher rates of any-grade fatigue (43.5% vs 37.4%), hypertension (32.2% vs 26.6%), and falls (21.8% vs 19.0%). Skin rash occurred more frequently in the combination arm, and this predominantly related to apalutamide. Rate of cardiac disorders was about the same in both arms (19.0% vs 19.2%). Grade 5 TRAEs occurred in 3.5% of patients receiving the combination and 7.6% of those receiving placebo plus abiraterone.

ACIS: Takeaways

Daniel P. Petrylak, MD:
The ACIS trial showed that treatment with apalutamide plus abiraterone and prednisone yielded a 31% reduction in risk of radiographic PFS compared with abiraterone plus placebo in first-line treatment of mCRPC although OS outcomes were similar.10 Taken together, we can conclude that combination therapy does not improve survival in this patient population. I think that with 2 randomized trials showing no OS benefit for combination regimens (ACIS OS, P = .498; Alliance A031201 OS, two-sided P = .53) answers the question as to whether combination therapy as first‑line treatment is better.

SPARTAN: Apalutamide vs Placebo in nmCRPC

Daniel P. Petrylak, MD:
Now moving on to the phase III SPARTAN trial, which has been previously reported.11 This trial enrolled 1207 patients with nonmetastatic CRPC and a PSA doubling time of ≤10 months. Patients were randomized to receive apalutamide at 240 mg daily plus androgen-deprivation therapy vs placebo plus androgen-deprivation therapy. The primary endpoint of this trial, which has been met and previously reported at multiple meetings, was metastasis‑free survival (MFS). After a median follow-up of 20.3 months, median MFS was 40.5 months in the apalutamide arm and 16.2 months in the placebo arm (HR: 0.28; P <.001).11 The current analysis was looking to identify molecular signatures that may be associated with long‑term response.12 This is something we clearly need, because it will help us stratify our patients for future trials.

SPARTAN Biomarker Analysis: Methods

Daniel P. Petrylak, MD:
Patients in both arms were divided into quartiles and this was based upon the number and timing of metastatic events. The long‑term responders were those without progression or who reached metastatic event later (fourth quartile), and the early progressors were patients who had a metastatic event in the first quartile. A total of 233 patients underwent transcriptome analysis based upon a predefined set of molecular signatures, and the signatures associated with response or resistance to treatments were identified by parallel methods of analysis.

SPARTAN Biomarker Analysis: Results

Daniel P. Petrylak, MD:
In the apalutamide arm, increased immune activity and decreased vascularization or proliferative capacity were associated with long‑term responses. None of these were associated with long‑term responses in the placebo arm. Increased expression of signatures suggestive of T‑cell proliferation was associated with longer MFS in the apalutamide arm (HR: 0.43; 95% CI: 0.21-0.86; P = .0180) but not in the placebo arm (HR: 1.10; 95% CI: 0.57-2.11; P = .7825). Of note, luminal tumors had longer MFS than basal tumors when treated with apalutamide (HR: 0.40; 95% CI: 0.18-0.91; P = .0295). Basal tumors with a high T‑cell proliferation had similar MFS to luminal tumors, and basal tumors with low T‑cell proliferation had significantly lower MFS compared with luminal or high T‑cell tumors.

SPARTAN Biomarker Analysis: Takeaways

Daniel P. Petrylak, MD:
The SPARTAN biomarker analysis suggested that patients with nonmetastatic CRPC may experience long-term benefit from apalutamide if their tumors are associated with features of immune activity, hormone dependence, or lower proliferation at baseline.12 I think this is a good hypothesis for further stratification of our patients in future trials. 

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