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ASCO GU 2020: Dr. Petrylak Discusses Exciting Prostate Cancer and Bladder Cancer Data

Daniel P. Petrylak, MD
Published: Thursday, Mar 26, 2020



Daniel P. Petrylak, MD, professor of medicine and urology, co-leader of Cancer Signaling Networks, Yale Cancer Center, and 2017 Giant of Cancer Care® in Genitourinary Cancers, shares exciting prostate cancer and bladder cancer data presented at the 2020 Genitourinary Cancers Symposium.
 
One of the more exciting presentations was on the phase Ib/II EV-103 trial, which examined the addition of enfortumab vedotin-ejfv (Padcev) to pembrolizumab (Keytruda) in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-based chemotherapy, says Petrylak. Treatment with the combination led to an objective response rate of 73%. The antitumor shrinkage rate with the combination was 84%, which was particularly impressive, according to Petrylak. Enfortumab vedotin-ejfv alone has about a 70% antitumor shrinkage rate, Petrylak adds, suggesting that this is one of the more active combinations under investigation in this space. Furthermore, the median progression-free survival (PFS) with the combination was 12.3 months (95% CI, 7.98), which was also exciting, says Petrylak.

The phase II STAMP and STRIDE trials examined combinations of sipuleucel-T (sip-T) with different hormonal agents like abiraterone acetate (Zytiga) or enzalutamide (Xtandi), respectively, in patients with metastatic castrate-resistant prostate cancer (mCRPC). In research presented during a poster presentation during the symposium, investigators evaluated the correlation between humoral antigen spread with cytotoxic T lymphocyte activity after sip-T in those 2 trials. Investigators found that treatment with sip-T in patients with mCRPC appears to invoke the tumor immunity cycle, wherein tumor cell death releases antigens that act as secondary epitopes resulting in humoral antigen spread. Sipuleucel-T is an important product and a bit underused in mCRPC, because in the past, people thought there was no difference in PFS with the agent, says Petrylak. However, the IMPACT trial did demonstrate a survival benefit with sip-T in these patients who are either asymptomatic or minimally symptomatic, says Petrylak.
 
In the phase III COSMIC-021 trial, researchers assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics of cabozantinib (Cabometyx) in combination with atezolizumab (Tecentriq) in patients with multiple tumor types. Results from cohort 6 of the trial showed that, at a median follow-up of 12.6 months, the ORR with the combination was 32%, which included 2 complete responses, and 12 partial responses. In a subgroup of patients with high-risk clinical features, including visceral metastases and/or extra-pelvic lymph node metastases, the ORR was 33%. The median duration of response was 8.3 months and the median time to objective response was 1.6 months. The exciting thing about this research, aside from the response rates, is that when the drugs are used alone, they show minimal activity, but when combined, they show true synergy, says Petrylak. The combination has the most potential for use in those with visceral disease or in combination with chemotherapy, adds Petrylak.
 
Another randomized phase II trial studied the efficacy of olaparib (Lynparza) with or without cediranib in patients with mCRPC that has spread to other places in the body. Cediranib, a VEGF TKI, suppresses the expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to PARP inhibitors in vitrosays Petrylak. The median radiographic PFS with the combination was 11.14 months versus 4.00 months with olaparib alone (HR 0.542; 95% CI, 0.317-0.928; P = .026); that was determined to be statistically significant. Interestingly, one patient who was BRCA positive, had initially responded to olaparib and progressed was then put on the combination and responded again, adds Petrylak. The goal is to now expand the use of PARP inhibitors in more patients beyond those with BRCA mutations. 
 
Finally, the ongoing phase KEYNOTE-921 trial is assessing the efficacy and safety of the combination of pembrolizumab and docetaxel versus placebo plus docetaxel in the treatment of chemotherapy-naïve men with mCRPC. Patients enrolled on the trial have not received chemotherapy who have progressed on a next-generation hormonal agent. The trial is accruing patients nicely, says Petrylak, who adds that hopefully in 1 or 2 years, it will reveal whether this approach improves survival in these patients.
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Daniel P. Petrylak, MD, professor of medicine and urology, co-leader of Cancer Signaling Networks, Yale Cancer Center, and 2017 Giant of Cancer Care® in Genitourinary Cancers, shares exciting prostate cancer and bladder cancer data presented at the 2020 Genitourinary Cancers Symposium.
 
One of the more exciting presentations was on the phase Ib/II EV-103 trial, which examined the addition of enfortumab vedotin-ejfv (Padcev) to pembrolizumab (Keytruda) in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-based chemotherapy, says Petrylak. Treatment with the combination led to an objective response rate of 73%. The antitumor shrinkage rate with the combination was 84%, which was particularly impressive, according to Petrylak. Enfortumab vedotin-ejfv alone has about a 70% antitumor shrinkage rate, Petrylak adds, suggesting that this is one of the more active combinations under investigation in this space. Furthermore, the median progression-free survival (PFS) with the combination was 12.3 months (95% CI, 7.98), which was also exciting, says Petrylak.

The phase II STAMP and STRIDE trials examined combinations of sipuleucel-T (sip-T) with different hormonal agents like abiraterone acetate (Zytiga) or enzalutamide (Xtandi), respectively, in patients with metastatic castrate-resistant prostate cancer (mCRPC). In research presented during a poster presentation during the symposium, investigators evaluated the correlation between humoral antigen spread with cytotoxic T lymphocyte activity after sip-T in those 2 trials. Investigators found that treatment with sip-T in patients with mCRPC appears to invoke the tumor immunity cycle, wherein tumor cell death releases antigens that act as secondary epitopes resulting in humoral antigen spread. Sipuleucel-T is an important product and a bit underused in mCRPC, because in the past, people thought there was no difference in PFS with the agent, says Petrylak. However, the IMPACT trial did demonstrate a survival benefit with sip-T in these patients who are either asymptomatic or minimally symptomatic, says Petrylak.
 
In the phase III COSMIC-021 trial, researchers assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics of cabozantinib (Cabometyx) in combination with atezolizumab (Tecentriq) in patients with multiple tumor types. Results from cohort 6 of the trial showed that, at a median follow-up of 12.6 months, the ORR with the combination was 32%, which included 2 complete responses, and 12 partial responses. In a subgroup of patients with high-risk clinical features, including visceral metastases and/or extra-pelvic lymph node metastases, the ORR was 33%. The median duration of response was 8.3 months and the median time to objective response was 1.6 months. The exciting thing about this research, aside from the response rates, is that when the drugs are used alone, they show minimal activity, but when combined, they show true synergy, says Petrylak. The combination has the most potential for use in those with visceral disease or in combination with chemotherapy, adds Petrylak.
 
Another randomized phase II trial studied the efficacy of olaparib (Lynparza) with or without cediranib in patients with mCRPC that has spread to other places in the body. Cediranib, a VEGF TKI, suppresses the expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to PARP inhibitors in vitrosays Petrylak. The median radiographic PFS with the combination was 11.14 months versus 4.00 months with olaparib alone (HR 0.542; 95% CI, 0.317-0.928; P = .026); that was determined to be statistically significant. Interestingly, one patient who was BRCA positive, had initially responded to olaparib and progressed was then put on the combination and responded again, adds Petrylak. The goal is to now expand the use of PARP inhibitors in more patients beyond those with BRCA mutations. 
 
Finally, the ongoing phase KEYNOTE-921 trial is assessing the efficacy and safety of the combination of pembrolizumab and docetaxel versus placebo plus docetaxel in the treatment of chemotherapy-naïve men with mCRPC. Patients enrolled on the trial have not received chemotherapy who have progressed on a next-generation hormonal agent. The trial is accruing patients nicely, says Petrylak, who adds that hopefully in 1 or 2 years, it will reveal whether this approach improves survival in these patients.
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