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How to best pair immune checkpoint inhibitors with other agents known to have efficacy in genitourinary cancers was a key avenue of inquiry of many of the studies presented at the 2020 Genitourinary Cancers Symposium.
How to best pair immune checkpoint inhibitors with other agents known to have efficacy in genitourinary cancers was a key avenue of inquiry of many of the studies presented at the 2020 Genitourinary Cancers Symposium. Investigators presented findings from trials of immunotherapy in combination with PARP and tyrosine kinase inhibitors, antiandrogens, and other interventions.
Molecular characteristics of disease and mechanisms of resistance were other important topics at the interdisciplinary meeting, which featured more than 800 abstracts. Key opinion leaders spoke with OncologyLive® to share their insights on the most exciting and pivotal updates in genitourinary cancer. Interviews live from the 2020 Genitourinary Cancers Symposium can be viewed on the OncLive® News Network at onclive.com/link/7518.
Mary-Ellen Taplin, MD
Mary-Ellen Taplin, MD
Dana-Farber Cancer Institute
Time to second progression (PFS2) in patients (pts) from TITAN with metastatic castration-sensitive prostate cancer (mCSPC) by first subsequent therapy (hormonal vs. taxane). Abstract 82.
Early results from the phase III TITAN study (NCT02489318) suggest that adding apalutamide (Erleada) to androgen deprivation therapy (ADT) greatly reduces the risk of secondary disease progression in mCSPC versus ADT alone, regardless of whether patients received hormonal therapy or taxane as the first life-prolonging subsequent therapy.
In this post hoc analysis, investigators used progression-free survival (PFS) from randomization to disease progression on the first subsequent therapy or death, whichever came first (PFS2), as an exploratory end point. PFS2 is an indicator of effective early intensification of treatment. The treatment arms were apalutamide with ADT or ADT alone.
Findings showed apalutamide with ADT conveyed a significant PFS2 advantage versus ADT (HR, 0.66; 95% CI, 0.50-0.87; P = .0026). The benefit of the apalutamide-containing regimen was observed whether the first subsequent treatment was a hormonal therapy (HR, 0.684; 95% CI, 0.482-0.971; P = .0326) or taxane (HR, 0.634; 95% CI, 0.456-0.881; P = .0062). Median PFS2 was not reached in either arm.
TITAN enrolled 1052 patients with mCSPC, regardless of prior docetaxel administration or disease extent. Investigators of the posthoc analysis said hormonal therapy was the first subsequent therapy for 24 patients in the apalutamide arm and 62 in the ADT-only group. Taxane therapy was the first treatment for 30 and 69 patients in the experimental and control arms, respectively.
Taplin: In the data presented on a small number of [TITAN’s] whole cohort of patients, [which included] approximately 270 patients, it looked like PFS2 certainly held up with the apalutamide group compared with the ADT group. You might expect this: It might make sense because you get the extra therapy, apalutamide, with ADT instead of placebo. I think the caveat with this one is that there are very few events so far that can be measured. I think we’re going to feel good about giving earlier treatment that will correlate with PFS2 and overall survival. We need another year or 2 of data, but it’s a very good early look at [TITAN].
PROTEUS: A randomized, double-blind, placebo (PBO)-controlled, phase III trial of apalutamide (APA) plus androgen deprivation therapy (ADT) versus PBO plus ADT prior to radical prostatectomy (RP) in patients with localized high-risk or locally advanced prostate cancer (PC). Abstract TPS383.
The international, phase III PROTEUS trial (NCT03767244) will evaluate combination apalutamide and ADT given before and after radical prostatectomy (RP) to determine whether this approach improves the pathological complete response (pCR) rate and metastasis-free survival (MFS) more effectively than ADT alone in approximately 1500 patients with localized high-risk or locally advanced prostate cancer.
Patients randomized to apalutamide and ADT will receive 240 mg of apalutamide daily for 6 cycles before RP. After RP, patients will receive an additional 6 cycles of apalutamide. Those randomized to the ADT arm will receive placebo in place of apalutamide. Coprimary end points include pCR and MFS.
Taplin: Prostate cancer is 1 of the few cancers where we haven’t proven with data that combining systemic therapy with surgery improves outcomes. This trial is the first large phase III neoadjuvant trial in localized high-risk prostate cancer in 12 years and is based on preliminary data from a series of phase II trials looking at intense hormone therapy prior to prostatectomy.If this is a positive study, it could prove that the pathology end points are valid [and] could really open the door for a lot of other good work to be done in this space. The exciting news about this trial is that it is accruing much quicker than we had projected. It has been very well received by patients, treating urologists, and medical oncologists around the world. [The study will] will take 2 ½ years to accrue and another few years to follow, but we are really excited that this trial is getting done so quickly.
Daniel P. Petrylak, MD
Daniel P. Petrylak, MD
Yale Cancer Center
Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): results of Cohort 6 of the COSMIC-021 study. Abstract 139.
Encouraging results from the combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) in patients with mCRPC were observed in the phase I/II COSMIC-021 study (NCT03170960). Investigators sought to evaluate this combination to test the theory that cabozantinib can promote an immune-permissive microenvironment and increase response to immune checkpoint inhibitors such as atezolizumab.
Cohort 6 of COSMIC-021 enrolled 44 patients with mCRPC who had soft tissue radiographic progression after prior enzalutamide (Xtandi) with or without abiraterone acetate (Zytiga). The combination regimen had “clinically meaningful activity” with a tolerable safety profile, and demonstrated consistent activity in men with high-risk disease, investigators said.
The objective response rate (ORR) was 32% (80% CI, 23-42), which included 2 complete responses (CRs) and 12 partial responses (PRs). Among the 36 patients with high-risk disease, including visceral and/or extra pelvic lymph node metastases, the ORR was 33%.
In the overall population, the duration of objective response was 8.3 months (range, 2.8-≥9.8) and the time to objective response was 1.6 months (range, 1-7). The disease control rate (DCR) was 80%.
The findings support further study of combination cabozantinib and atezolizumab in this setting, investigators said. Consequently, cohort 6 is being further expanded and other cohorts have been added to COSMIC-021. The synergy of the dual-drug approach will be explored in a phase III trial that is being planned in this disease setting.
Petrylak: Cabozantinib is a [receptor tyrosine] kinase [inhibitor] that decreases myeloid suppressor cells, so it has an immune modulatory effect. By itself, cabozantinib did not improve survival in randomized trials in castration-resistant prostate cancer. For atezolizumab, [the response rate] is less than 10%. When you combine the drugs, you get about a 30% response rate. This is incredibly exciting, because 2 drugs that have minimal activity separately are now showing activity when combined. There is true synergy.
If you look at the spider plots, what you will see in a lot of these patients is an increase in tumor volume and then a decrease, which tells me this is probably an immune mechanism. The cancer cells or the immune cells are migrating toward the measurable disease, [promoting] antitumor activity, and causing the cancer cells to die. I think there are a lot of interesting questions mechanistically with this combination, which potentially affords us another option, [perhaps] in place of chemotherapy or after chemotherapy.
These are patients with poor-risk characteristics. As we treat more patients down the continuum, we are seeing the disease get more aggressive, we are seeing more liver metastases and more disease spread to other areas. The most impressive response in this study was a patient who had a complete response in the liver, which, outside of platinum [-based chemotherapy], is not really seen. I think that there is great potential for this combination either in visceral disease, in combination with chemotherapy, or in other areas.
The association of humoral antigen spread (AgS) with cytotoxic T lymphocyte (CTL) activity after sipuleucel-T (sip-T) treatment in 2 phase II clinical studies: STAMP and STRIDE. Abstract 112.
Sipuleucel-T (sip-T; Provenge) may play a more profound role in stimulating immune response than previously thought, based on results from the phase II STAMP (NCT01487863) and STRIDE (NCT01981122) trials.
Armed with the knowledge that sip-T prompts humoral antigen spread (AgS) and cytotoxic T lymphocyte (CTL) activity, STAMP and STRIDE investigators evaluated whether treatment with the immunotherapy could generate a secondary antibody response, extending anticancer activity and improving overall survival (OS) in patients with mCRPC. STAMP evaluated sip-T concurrently versus sequentially with abiraterone acetate and prednisone while STRIDE assessed sip-T concurrently versus sequentially with enzalutamide.
In both trials, investigators observed CTL activity and AgS responses to primary antigens (PA2024, prostatic acid phosphatase [PAP]) and secondary antigens (prostate-specific antigen [PSA], LGALS3, LGALS8, KRAS, ERAS, KLK2). Across both studies, PA2024-specific CTL activity at week 26 positively correlated with antibody response to 2 primary antigens, P2024 and PAP, and 4 secondary antigens, PSA, KRAS, ERAS, and KLK2, at multiple time points.
Findings from the phase III IMPACT trial (NCT00065442) of sip-T in patients with metastatic prostate cancer, which was completed in 2010, showed that increased antibody responses to nontargeted secondary antigens such as LGALS3, LGALS8, PSA, KLK2, ERAS, and KRAS correlated with improved OS. STAMP and STRIDE investigators observed similar activity with sip-T and concluded that the therapy appears to invoke the tumor immunity cycle, engendering tumor cell death that leads to antigen release. These antigens act as secondary epitopes, allowing for humoral AgS and, potentially, improved OS, investigators said.
Petrylak: STAMP and STRIDE looked at combinations of sip-T with different hormonal agents, including enzalutamide, abiraterone, or prednisone. In the studies, we observed the different patterns of immunity that developed with sip-T treatment. Sip-T is a dendritic cell product that targets PAP. We thought this was all predominantly a dendritic cell process, but what we are seeing as time goes on is that there is something called antigen spread [in which] the cancer cells are basically lysed. These cells release antigens aside from PAP, including PSA, PSMA [prostate-specific membrane antigen], and prostate stem cell antigen. A variety of antigens are expressed.Later, the cancer cells develop B-cell immunity to those particular targets, so there may be 2 different ways that sipuleucel-T induces cellular death. Sip-T is an important product that I think is underused in CRPC, mainly because in the past, people thought there wasn’t a PFS difference [with the therapy], but now as we’re seeing with immunotherapy, you don’t need a PFS difference to get a survival benefit. The IMPACT trial, which is now almost 10 years old, demonstrated a survival benefit since its initial publication for sipuleucel-T in patients with symptomatic or minimally symptomatic disease.
Matthew D. Galsky, MD
Matthew D. Galsky, MD
The Tisch Cancer Institute
Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB trial. Abstract 542.
Findings from the phase II NEODURVARIB study (NCT03534492) of durvalumab (Imfinzi) and olaparib (Lynparza) prior to surgery demonstrated that in patients with resectable muscle-invasive bladder carcinoma (MIBC) the neoadjuvant combination induced a pCR rate of 50%. pCR was defined as absence of tumor in the bladder and lymph nodes.
In MIBC, response rates to single-agent immune checkpoint inhibition typically do not exceed 30%, according to lead author, Juan Francisco Rodriguez-Moreno, MD, PhD. In his presentation, he described the pCR data as very interesting, because the study was not designed to assess the efficacy of the combination. Rather, NEODURVARIB was initiated to evaluate the impact of the neoadjuvant doublet on the molecular profile of MIBC.
The biomarker data and the molecular characterization information are currently being analyzed and may be available at the European Society for Medical Oncology 2020 Congress in September, Rodriguez-Moreno, a medical oncologist at HM Hospitales—HM CIOCC in Madrid, Spain, added.
The standard of care for MIBC is radial cystectomy, which is rarely curative, according to Rodriguez-Moreno. Cisplatin-based chemotherapy is the perioperative standard, but few patients benefit from this approach, creating a need for additional neoadjuvant options.
Safety data from NEODURVARIB indicated that the combination was well-tolerated: There were only 3 grade 4 adverse events (AEs) and only 3 treatment interruptions in the 27 patients evaluated for safety. Infections and wound evisceration were the most common grade 3 AEs and affected 18.5% and 7.4% of patients, respectively. Other grade 3 AEs included anemia, neutropenia, asthenia, hematuria, pulmonary embolism, and hypertension, each of which affected 3.7% of patients. NEODURVARIB enrolled 29 patients with cT2 to T4a resectable MIBC who were treated for 6 to 8 weeks prior to planned cystectomy with durvalumab 1500 mg administered every 4 weeks for a maximum of 2 months. Investigators gave olaparib 150 mg twice daily for up to 56 days.
Galsky: It is very timely that these data were presented at this meeting. We need treatments for patients who are cisplatin-ineligible in the neoadjuvant setting, and we know that neoadjuvant immune checkpoint blockade alone results in pathologic complete responses in [about] 30% of patients. However, that is not 100% of patients, so we want to build on that. From this meeting, we learned that if you give a PARP inhibitor to patients with metastatic bladder cancer, [you will not see] a lot of activity in patients who already received platinum-based chemotherapy. This might be because the mechanisms of resistance are similar.Using a regimen [that includes] a PARP inhibitor and an immune checkpoint inhibitor in patients who have not had any platinum-based chemotherapy makes a lot of sense from the standpoint of independent drug action. Also, model systems based on laboratory data [suggest] that PARP inhibition might cause immunomodulatory effects beyond direct cell kill.
Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy. Abstract 439.
A triplet therapy consisting of nivolumab (Opdivo), gemcitabine, and cisplatin demonstrated impressive efficacy in MIBC in the phase II BLASST-1 study (NCT03294304). The neoadjuvant regimen induced a pCR of 49% and pathologic responses in 66% (27) of the trial’s 41 patients with MIBC. Importantly, there were no delays to cystectomy, unexpected surgical complications, added toxicities, or deaths with the combination, investigators said.
Less than half (39%; 15 of 39) of tumors assessed were PD-L1 positive. Pathologic response was observed in 71% (17 of 24) of patients with PD-L1—negative tumors and 67% (10 of 15) of patients with PD-L1–positive tumors. A biomarker analysis is ongoing and will shed light on the predictors of response and resistance to chemoimmunotherapy in MIBC, investigators said.
They added that long-term follow-up, in addition to results from an ongoing confirmatory trial, the phase III ENERGIZE study (NCT03661320), will provide additional insight.
Galsky: Combining chemotherapy with immune checkpoint blockade in the neoadjuvant setting before definitive surgery is an approach that is being explored in many randomized phase III studies. Those studies [moved] quickly without having a lot of phase II study data, which is why a study like this is so important to [help] understand the activity of these regimens.We have the first randomized data set in the metastatic setting and know that if you give chemotherapy and immune checkpoint blockade, you can significantly improve PFS compared with chemotherapy alone. We do not have final survival data from this yet, but one can take that concept and move it into the neoadjuvant setting. It is a very logical treatment strategy: 2 classes of treatments that work differently and we combine them [to derive benef it from the different mechanisms of action]. So far, we only have 1 data set that has been presented combining chemotherapy and immune checkpoint blockade in the neoadjuvant setting, and that was gemcitabine, cisplatin, and pembrolizumab. The BLASST-1 study is evaluating gemcitabine, cisplatin, and nivolumab. It is going to be important in making sure we are on the right track with the other phase III studies.
Brian Rini, MD
Brian I. Rini, MD
Vanderbilt-Ingram Cancer Center
Nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in pretreated patients (pts) with metastatic renal cell carcinoma (mRCC): First results of phase II NIVES study. Abstract 613.
In the phase II NIVES study (NCT03469713), a high DCR and no increase in toxicity were demonstrated with the combination of nivolumab and stereotactic body radiotherapy (SBRT) in 69 patients with mRCC. Findings from NIVES, which is the first prospective trial of this regimen in patients with mRCC, showed that the combination had an acceptable safety profile and did not lead to an increase in treatment interruption compared with nivolumab monotherapy. Although NIVES did not reach its primary end point of ORR at 36 months, the DCR (58.0%) and 12-month OS rate (73.4%; 95% CI, 60.6-82.6) were both high with combination nivolumab and SBRT, investigators said.
The ORR was 17.4% (95% CI, 9.3-28.4) and included 1 complete response and 11 PRs. The median PFS was 4.1 months (95% CI, 2.8-7.1) and the 12-month PFS rate was 32.6% (95% CI, 21.0-44.6). Additionally, the median OS was 22.07 months (95% CI, 18.1-not reached).
The correlative analysis of treatment efficacy and PD-L1 expression is ongoing. NIVES’ findings, different timing of SBRT, and the addition of ipilimumab (Yervoy) “could be considered” in further studies, investigators said.
Rini: There were a couple trials that looked at radiotherapy in combination with nivolumab. NIVES uses SBRT, which became useful in lung cancer over the past decade. Now it is being used in metastatic [disease], including kidney cancer. The theory is that by radiating the tumor, you get antigen release, which increases the immune response when you give an immune agent, leading to more systemic tumor immunity.It is not clear from the trials [presented] that the activity seen was any more than you would have expected from the immunotherapy alone, so I am not convinced that SBRT is a way to increase antitumor immunity. I think the field is figuring out what to do with it. Having said that, I use SBRT in my own practice. I use it more and more, although I always struggle when I give it to a patient and ask myself, “Am I really helping this patient? Am I making them live better or longer by doing this?” I am not sure that there are definitive data. These are interesting studies, but I think more work needs to be done, because SBRT is a new tool.
Overall survival and independent review of response in CheckMate 214 with 42-month follow-up: first-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). Abstract 609.
Data from a 42-month follow-up of the phase III CheckMate 214 trial (NCT02231749) demonstrated prolonged survival and response rates with combination nivolumab and ipilimumab versus sunitinib monotherapy in patients with intermediate or poor-risk mRCC. CheckMate 214 is the longest follow-up of a phase III study of an immunotherapeutic combination for the first-line treatment of patients with advanced RCC.
The study enrolled 1096 patients with treatment-naïve advanced or metastatic RCC, 550 of whom were randomized to the combination regimen. The remaining 546 of the intention-to-treat (ITT) population received single-agent sunitinib therapy. Of the 550 patients treated with the combination, 425 had intermediate- or poor-risk disease, as did 422 of the 546 patients randomized to sunitinib. Data from CheckMate 214 at an earlier, 17.5-month follow-up indicated a significant survival advantage with nivolumab and ipilimumab and led to the regimen’s approval as a frontline therapy for patients with intermediate or poor-risk disease, in 2018.
At a minimum 42-month follow-up, median OS for patients with intermediate or high-risk disease was 47.0 months (95% CI, 35.6-not estimable) for nivolumab and ipilimumab versus 26.6 months (95% CI, 22.1-33.5) for sunitinib (HR, 0.66; 95% CI, 0.55-0.80; P <.0001).
After 30 months, the PFS curves plateaued at approximately 35% with the combination in the intermediate/poor-risk and ITT groups. For the intermediate and poor-risk population at the 42-month minimum follow-up, median PFS was 35% (12.0 months 95% CI, 8.7-15.5) with nivolumab/ipilimumab versus 19% (8.3 months 95% CI, 7.0-11.1) for sunitinib (HR, 0.76; 95% CI, 0.63-0.91; P <.01).
Most CRs and PRs observed with nivolumab and ipilimumab were ongoing: 121 of the 179 patients (68%) receiving the immunotherapy doublet had an ongoing response, versus 58 of the 111 patients (52%) in the sunitinib arm. A CR rate >10% was consistently seen with nivolumab and ipilimumab across risk subgroups. The ORRs were 42% and 26% for the combination and the monotherapy groups, respectively.
Treatment-related adverse events (TRAEs) declined over time, and no new toxicities emerged with the combination, investigators said. Moreover, OS was not affected in patients who discontinued the regimen due to TRAEs.
Rini: One of the nice things about this data set is it has the longest follow-up of the phase III trials. This was a 42-month follow-up, getting us on to the 3- to 4-year range. This is an all immune combination and the strength of immunotherapy, especially dual immunotherapy, is durability of response. With this long-term follow-up, we are starting to see patients who are in remission. The PFS rate at the 42-month mark was around 35%, so it means that one-third of patients you start on therapy are still going to have disease control 3 ½, 4 years later. That is amazing for kidney cancer, so I think that is the real value in this data set. A lot of the other numbers did not change. Hazard ratios and PFS were consistent. As this data set further matures, I think we will see more and more durability.
Full abstracts are available for reference at: bit.ly/2TdFwFN.