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Daniel P. Petrylak, MD, discusses important new developments in bladder and prostate cancer.
Daniel P. Petrylak, MD, professor of Medicine and Urology, co-director, Signal Transduction Research Program, Yale School of Medicine
Daniel P. Petrylak, MD
Less than a decade ago, it was difficult to get pharmaceutical companies interested in conducting trials in bladder cancer. Thanks to breakthrough treatments pioneered by investigators such as Daniel P. Petrylak, MD, that has changed. Anti—PD-1/PD-L1 agents helped open the door to better outcomes, and most recently the FDA granted accelerated approval to enfortumab vedotin-ejfv (Padcev), an antibody-drug conjugate that demonstrated an overall response rate (ORR) of 44% in patients with locally advanced or metastatic urothelial cancer in the EV-201 trial (NCT03219333).1,2
“The best responder in the phase I trial had a complete response despite starting with metastases to the liver,” said Petrylak, who helped lead the investigation of the novel compound. “She is still alive and still showing complete response 3.5 years after starting treatment. I have never seen anything like that in bladder cancer. Never.”
An intrepid investigator and a 2017 Giants of Cancer Care® award winner whose motto is “never quit,” Petrylak describes drug development in genitourinary (GU) malignancies as his passion (Table1,3,4).
He is a professor of medicine and urology at Yale School of Medicine and codirector of the Cancer Signaling Networks Research Program at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut. He also is cochair of this year’s 13th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, taking place March 13 to 14 in New York, New York.
In an interview with OncologyLive®, Petrylak discussed important new developments in bladder and prostate cancer and the agenda for the symposium, which will provide a comprehensive overview of GU malignancies with a focus on urothelial, prostate, and renal cancers. Topics will include diagnostic molecular pathology, current and evolving therapeutic strategies, and best practices for managing advanced disease.
This year’s meeting is cochaired by Leonard G. Gomella, MD, FACS, the Bernard W. Godwin Jr Professor of Prostate Cancer and chairman of the Department of Urology at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania.
Gomella is also senior director of clinical affairs and coleader of the Prostate Cancer Program at the Sidney Kimmel Cancer Center and clinical director of the Sidney Kimmel Cancer Center Network.
The FDA’s December 2019 approval for enfortumab vedotin came nearly 15 years after docetaxel (Taxotere) became the first approved treatment for metastatic castration- resistant prostate cancer (mCRPC), a breakthrough in which Petrylak also played a role.
Petrylak began in vitro experiments with enfortumab vedotin 8 years ago and stuck with the agent through the phase II trial that earned it accelerated approval as a second-line therapy for adult patients with previously treated locally advanced or metastatic urothelial cancer.
“The alternative treatment in bladder cancer is immune therapy, but only about 1 in 4 patients responds to that, so there was a significant unmet need, which allowed for the accelerated approval with enfortumab,” Petrylak said.
The approval is based on results from the first cohort of patients in the phase II EV-201 trial, which showed that enfortumab vedotin elicited a complete response (CR) rate of 12% and a partial response (PR) rate of 32% in patients who have received prior treatment with a PD-1/PD-L1 inhibitor used with (cohort 1) or without (cohort 2) platinum- containing chemotherapy.1
A total of 128 patients were enrolled for cohort 1. They received 1.25 mg/kg of intravenous enfortumab vedotin on days 1, 8, and 15 of each 28-day cycle. Overall survival (OS) was 11.7 months (95% CI, 9.1—not reached), the median progression- free survival (PFS) was 5.8 months (95% CI, 4.9-7.5), and the median duration of response (DOR) was 7.6 months (range, 0.95- ≥11.3).
The most common treatment-related adverse events (TRAEs) of any grade were fatigue (50%), alopecia (49%), and decreased appetite (44%), and the most common TRAEs of grade 3 or above were rash (12%), hyperglycemia (6%) and peripheral neuropathy (3%). The treatment discontinuation rate due to TRAEs was 12%, which was mostly a result of peripheral neuropathy.1
The results from EV-201’s cohort 1 were not the first success for enfortumab vedotin. The FDA granted the medication a breakthrough therapy designation in March 2018 based on results from the EV-101 trial. Updated results from that study, which included a median follow-up of 13.4 months on 112 patients with previously treated metastatic urothelial cancers, showed an ORR of 42%, including CR in 5 patients and PR in 42 patients.
Among responders, median DOR was 7.7 months (95% CI, 5.6-9.6) and 23.4% of responses were ongoing after a median follow-up of 11.3 months. The estimated median PFS was 5.4 months (95% CI, 5.1-6.3), whereas the estimated OS was 12.5 months (95% CI, 9.3-16.1). The OS rate at 1 year was 51.8%.5
“The phase I trial and the phase II trial both demonstrated roughly the same level of activity, which was remarkable when compared to any other available treatment for these patients. These numbers are unprecedented,” said Petrylak, who added that although adverse effects were comparable between chemotherapy and enfortumab vedotin, the newer treatment seems to be better tolerated by most patients.
By comparison with enfortumab vedotin, response rates to second-line PD-1/PD-L1 inhibition are 13% to 21%, and there are few options post progression. Single-agent chemotherapy after platinum and before PD-1/PD-L1 inhibition has an ORR of roughly 11%.1,5
Novel Agents Multiply
Antibody-drug conjugates such as enfortumab vedotin are dual-action molecules. After the antibody binds to some part of the targeted disease, the drug is released and it attacks the cancer. Enfortumab vedotin binds to nectin-4, a surface protein that is highly expressed in bladder cancer. It then releases the antitumor agent monomethyl auristatin E, which blocks reproduction and can trigger cell death.
Even in the setting of refractory bladder cancers, enfortumab vedotin could help a significant number of patients. Bladder cancer killed an estimated 17,670 patients in the United States last year. The drug could be even more useful if it succeeds in trials that are planned to measure its efficacy in patients with earlier-stage disease. Roughly 80,000 Americans received a bladder cancer diagnosis last year, and about half of those diagnoses were made after the cancer had spread beyond the inner layer of the bladder wall.6
“There are a very significant number of patients who had no real treatment options before enfortumab who now have an option that has produced very significant results in these trials,” said Petrylak, who confirmed that the phase III trial that is needed to gain enfortumab vedotin full FDA approval is already under way. There are also ongoing early stage trials in patients with newly diagnosed, locally advanced or metastatic urothelial cancer. “It’s an exciting treatment,” said Petrylak.
Bladder cancer is a logical target for antibody-drug conjugates because targetable driver mutations may be absent, but Petrylak’s other main focus, prostate cancer, offers more opportunities for direct attack. In 2015, investigators showed that 90% of prostate cancers have actionable molecular targets. Approximately 20% involved defects in the DNA damage repair (DDR) genes BRCA1, BRCA2, or ATM.7
Such genes repair DNA by activating PARP, which prompted investigation into whether PARP inhibitors could be used to treat prostate cancers. Successful early trials have led to a number of ongoing phase III trials that Petrylak ranks among the most promising prostate cancer research.
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The TOPARP-B trial (NCT01682772) randomized 98 patients with pretreated mCRPC and DDR gene aberrations to either 400 mg or 300 mg of olaparib twice daily. After a median follow-up of 24.8 months, confirmed composite response was achieved in 25 of 46 evaluable patients (ORR, 54.3%; 95% CI, 39.0%- 69.1%) in the 400-mg cohort, and 18 of 46 evaluable patients (ORR, 39.1%; 95% CI, 25.1%-54.6%) in the 300-mg cohort. Subgroup analysis of specific gene alterations showed an ORR of 83.3% for BRCA1/2, 57.1% for PALB2, and 36.8% for ATM. The overall median PFS was 5.4 months.9
PARP inhibitors have delivered impressive results in other trials, Petrylak noted.
Initial results from a phase III trial of olaparib in patients with heavily pretreated mCRPC, the PROfound study (NCT02987543), were presented at the 2019 meeting of the European Society of Medical Oncology (ESMO). Investigators randomized 245 patients with BRCA1/2 or ATM alterations on a 2:1 basis to receive either olaparib (n = 162) or physician’s choice of abiraterone acetate (Zytiga) with prednisone or enzalutamide (Xtandi; n = 83). The median rPFS was 7.39 months in the olaparib arm and 3.55 months in the control arm (HR, 0.34; 95% CI, 0.25-0.47; P <.0001). The 12-month rPFS rates were 40% in the olaparib arm and 11% in the control arm. Median OS was 18.5 months in the olaparib arm and 15.11 months in the hormonal arm, but the OS data were affected by the crossover of 80.6% of the patients.10
Other PARP inhibitors are also being tested in patients with prostate cancer.
A phase II study dubbed TRITON2 (NCT02952534) tested rucaparib (Rubraca) in pretreated patients with mCRPC and a deleterious DDR gene alteration. As of February 28, 2019, 190 patients had been treated with rucaparib, which received the FDA’s breakthrough therapy designation on the strength of earlier TRITON2 results. After a median follow-up of 13.1 months, 43.9% of patients with a BRCA mutation had a confirmed ORR; the majority of responses had lasted >24 weeks. The ORR was lower for other mutation groups: The response rate was 9.5% for patients with ATM and 0% for patients with both CDK12 and CHEK2.11 The phase III TRITON3 study (NCT02975934) is under way.
Another phase II trial, GALAHAD (NCT02854436), is testing niraparib (Zejula) in patients with mCRPC and biallelic DNA-repair gene defects. According to results presented at the 2019 meeting of the American Society of Clinical Oncology (ASCO), the ORR was 37.5% in patients with BRCA1/2 mutations and 13.3% in the non-BRCA group.12
Beyond PARP Monotherapy
In addition to the many trials that are using PARP inhibitors as monotherapy for mCRPC, there are at least 3 large trials that are using PARP inhibitors in combination with other agents.
PROpel (NCT03732820) is a phase III trial comparing olaparib and abiraterone with placebo and abiraterone in pretreated patients with mCRPC or without DDR defects.13 It follows a phase II study in 142 patients, who were randomly assigned to receive olaparib and abiraterone (n = 71) or placebo and abiraterone (n = 71). Median rPFS was 13.8 months (95% CI, 10.8- 20.4) with olaparib and abiraterone and 8.2 months (95% CI, 5.5-9.7) with placebo and abiraterone.14
TALAPRO-2 (NCT03395197) is a phase III study comparing talazoparib and enzalutamide against placebo and enzalutamide in pretreated mCRPC with or without DDR defects. The main part of the trial is still enrolling patients, but investigators did report results from the initial part of the trial, which was designed to establish proper dosage, at ASCO 2019.15
MAGNITUDE (NCT03748641) is comparing niraparib and abiraterone with placebo and abiraterone in patients with mCRPC, divided into 2 cohorts of patients with and without DDR defects.16
Petrylak believes the PARP inhibitor trials will probably prove more important than the relatively recent approvals of the androgen-receptor blockers enzalutamide (Xtandi) and apalutamide (Erleada) for patients with metastatic castration-sensitive prostate cancer. Apalutamide and enzalutamide were approved in 2018 for CRPC.17,18
“Having medications approved for use in several different stages of disease creates questions about when is the best time to use them. And there no answers yet,” Petrylak said. “There are also questions about whether these medications are any better than alternatives that do similar things.”
Both apalutamide and enzalutamide extended radiographic PFS over placebo in the trials that won them the castration-sensitive indication, but apalutamide’s trial results also indicated improved OS. At the time of a prespecified interim analysis, the HR for OS was 0.67 (95% CI: 0.51-0.89; P = .0053) in the apalutamide arm of the TITAN trial (NCT02489318), even though median OS had not been reached in either arm.19
Follow-up analysis of the phase III SPARTAN trial (NCT01946204), which won apalutamide its indication for nmCRPC, also showed evidence of survival benefit. At 41 months of median follow-up and 285 deaths, apalutamide was associated with a 0.75 HR for death compared with placebo (95% CI, 0.59-0.96; P = .0197).20
Enzalutamide (PREVAIL, NCT01212991) has also demonstrated better OS than placebo in men with mCRPC, and it won FDA approval as first-line treatment for men who have not received chemotherapy or who have previously received docetaxel. However, it has not demonstrated superior OS compared with other approved treatments in men with mCRPC.21
“It’s just another drug in metastatic disease. Abiraterone and prednisone had already been approved in that situation, and it’s another treatment option that we can use. It seems to be similar survival overall,” said Petrylak.
He has higher hopes for prostate specific membrane antigen (PSMA)-directed diagnosis and therapy. PSMA is highly expressed in poorly differentiated CRPC. Several studies have found that PSMA PET/CT is significantly more sensitive than other imaging modalities such as choline PET/CT in detecting prostate cancer metastases in both soft tissue and bone. PSMA PET/CT is positive for about 50% of patients with a prostate specific antigen (PSA) level in the range of 0.5-1.0 μg/L and for more than 75% of patients with PSA recurrence and PSA >1 μg/L.22 At least 1 study has found that restaging with PSMA PET/CT localizes the site of recurrence for many recurrent patients with PSA levels of 0.2-0.5 μg/L, when local salvage therapies are still effective.23
In addition, PSMA can be used as a target for antibody-drug conjugates that latch on and deliver therapeutic agents. The best studied of these treatments is lutetium-177 (177Lu)— PSMA-617 radioligand therapy (RLT). A 2019 metaanalysis included 16 studies of Lu-PSMA RLT. Among the 671 patients in those studies, 493 experienced PSA decline and 307 experienced PSA declines of 50% or more.24
Big Strides in Prostate and Bladder Cancer
Today’s abundance of promising prostate cancer treatments stands in stark contrast to the dearth of such treatments in Petrylak’s early days as a researcher. There was no approved treatment for CRPC in 1996, when Petrylak discovered that docetaxel (Taxotere) combined with estramustine demonstrated activity against the disease. Petrylak and his colleagues wanted to examine further, so they designed a phase I trial and raised the money to fund it. The first patient didn’t respond at all, and Petrylak began to have doubts, but the next 5 or 6 patients did well.
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Advanced bladder cancer had a similar dearth of treatments until much more recently, but trials reported over the past few years have secured approvals for agents other than enfortumab vedotin. A large number of immune checkpoint inhibitors (ICIs)—atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), pembrolizumab (Keytruda) and nivolumab (Opdivo)— have won approvals for bladder cancer treatment, although they have utility for only about 25% of patients.
Ongoing trials are trying to boost response rates and increase the strength and duration of response by pairing individual ICIs with chemotherapy and by pairing the ICIs nivolumab and ipilimumab (Yervoy). Preliminary results for the ICI combination have not shown a dramatic increase in ORR, however.
An ORR of 37% was reported from a phase II study (NCT03333616) of nivolumab and ipilimumab in 19 patients with bladder cancers of variant histologies who received prior chemotherapy but not ICIs.25
The other big approval in ureothelial treatment last year was for erdafitinib (Balversa), the first targeted agent ever approved for bladder cancer. The accelerated approval was for adult patients with locally advanced or metastatic bladder cancer with FGFR3 or FGFR2 mutations that has progressed during or following prior platinum-containing chemotherapy. The FDA’s decision hinged upon a study (NCT02365597) in 87 such patients that reported an ORR of 32.2%.26
Looking Ahead
Petrylak maintains a busy clinical practice, which, according to some of his colleagues, is a key to his success as an investigator.
“Seeing a lot of patients contributes greatly to being a good clinical researcher. It gives you insights into the nuances of the disease, what’s important and what’s needed for patients,” said Celestia S. Higano, MD, FACP, a professor of both oncology and urology at the University of Washington School of Medicine who frequently collaborates with Petrylak. “Dan has led clinical trials in both prostate and bladder cancer for years in addition to maintaining a large clinical practice. I think that has kept him very focused on research that improves clinical outcomes.”
Petrylak has long ranked among the most respected researchers who specialize in prostate cancer and other GU malignancies.
“I have had the pleasure of knowing and collaborating with Dan from the days when we both were junior faculty in the early 1990s, both through SWOG and outside of it, and it has always been a great experience to work with him,” said Maha H. Hussain, MD, a 2015 Giants of Cancer Care® award winner in GU cancers and the deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
“He’s very thoughtful. He understands comprehensively what type of research is needed to make an impact. He has led and been part of many drug development efforts and large-scale trials that have led to drug approvals and improving standards of care for our patients.”
The group presented their results at the next Southwest Oncology Group (SWOG) Intergroup meeting, then embarked on the phase III trial SWOG 9916, which helped make docetaxel the first approved treatment for mCRPC.
Results from the first significant trial (TOPARP-A) appeared in 2015. Investigators used olaparib (Lynparza) in 49 patients with heavily pretreated mCRPC and detected some response in 16 of those patients (ORR 33%; 95% CI, 20%-48%), but the rates of response were much higher in cancers with certain genetic profiles. Responses were detected in 14 of 16 patients with homozygous deletions, deleterious mutations, or both in DNA-repair genes—including BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2. All 7 patients with BRCA2 loss responded.8
“A number of randomized trials with PARP inhibitors are showing an improvement in radiographic progression-free survival in patients who have been treated with them,” Petrylak said. “None of them are approved yet, but I think they’re likely to make a significant improvement in treatment.”