AR Pathway Inhibitors, ADCs, and IO/TKI Combinations Shape Standard Therapy in GU Cancers

Chandler Park, MD, MSc, FACP

Further research into biomarker testing, prostate-specific membrane antigen (PSMA) PET scans, and triplet therapies with androgen receptor (AR) pathway inhibitors are defining optimal therapies for patients with prostatecancer, according to Chandler Park, MD, MSc, FACP.

“We have all these great technologies, all the different precision treatments, in genitourinary [(GU) oncology],”Park said in an interview with OncLive® following an OncLive®State of the Science Summit™, which he chaired.

In the interview, Park, the codirector of Genitourinary Clinical Trials at Norton Cancer Institute in Louisville, Kentucky, discussed the evolution of metastatic hormone-sensitive prostate cancer (mHSPC) treatment, shifting definitions of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC), the importance of antibody-drug conjugates (ADCs) in bladder cancer, and the future of biomarkers in renal cell carcinoma (RCC).

The phase 3 ARASENS trial (NCT02799602), which investigated the AR pathway inhibitor (ARPi) darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) and docetaxel in patients with mHSPC, showed that the combination produced a 32.5% reduction in the risk of death vs placebo plus ADT and docetaxel.1In the phase 3 TITAN trial (NCT02489318), treatment with apalutamide (Erleada), another AR pathway inhibitor, plus ADT led to a 48-month overall survival (OS) rate of 65.1% vs 51.8% with placebo plus ADT in patients with metastatic CRPC (mCRPC).2 Park expanded on how this information is redefining the standards of care (SOC) across prostate cancer and highlighted similarly nuanced treatment options in other GU cancers.

OncLive®: How has the mHSPC treatment arena changed to include more effective therapies?

Park: There have been many advances in mHSPC in the last 8 years. From the 1970s until 2015, the SOC was ADT. In 2015, the randomized, phase 3 CHAARTED study[NCT00309985]of docetaxel with ADT vs ADT showed an OS benefit with docetaxel and ADT. That doublet treatment became the new SOC. Docetaxel can cause some tough adverse effects [AEs], being a chemotherapy.

In 2017, the randomized, phase 3 LATITUDE trial[NCT01715285]studied abiraterone acetate [Zytiga]with prednisone and ADT. This was the beginning of AR pathway inhibitors. LATITUDE showed that an ARPi inhibitor, in this case, abiraterone acetate, with prednisone [plus ADT] was superior to ADT, with an OS benefit.

In 2019, we had apalutamide, another AR pathway inhibitor, with ADT. InTITAN, apalutamide with ADT showed a survival benefit vs ADT. Notable in this study, TITAN showed a meaningful survival benefit for high volume and low volume mHSPC. After that were other [phase 3] studies like ENZAMET [NCT02446405] and ARCHES [NCT02677896]. [Treatment has evolved from] singlet treatment with ADT to doublet therapies, whether with chemotherapy plus ADT, or an AR pathway inhibitor, like abiraterone acetate, apalutamide, or enzalutamide [Xtandi], with ADT.

The question [then became]: What is the role of chemotherapy plus an AR pathway inhibitor with ADT? Is triple therapy better than doublet therapy? That was the research question behind the ARASENS study. Our team at Norton Cancer Institute was the #1 enroller in the US for this study, and I was very fortunate to be the principal investigator at our site. This study was released in the New England Journal of Medicine on March 24, 2022. [The ARASENS regimen] was FDA approved in August 2022.

ARASENS studied SOC docetaxel plus ADT (doublet therapy) vs the AR pathway inhibitor (Darolutamide), docetaxel, and ADT. This study randomized 1300 patients across the world and found that triplet therapy with an AR inhibitor, docetaxel, and ADT showed a survival benefit over docetaxel with ADT. This is considered a SOC for many patients newly diagnosed mHSPC today.

However, in TITAN, Neeraj Agarwal, MD, [of the University of Utah in Salt Lake City], also showed a survival benefit with apalutamide and ADT in patients with high- and low-volume disease with doublet therapy alone. Based on CHAARTED, patients with high-volume disease have 4 or more bone lesions, 1 being outside the axial skeleton. For instance, cancer in the femur or the humerus is considered high volume if 1 of the 4 lesions is outside of the axial skeleton or patients have metastatic disease in the liver or lung. Based on updated information from the TITAN study, ARASENS study may have been more complete if SOC arm for ARASENS was an AR pathway inhibitor, Docetaxel, and ADT vs AR pathway inhibitor and ADT. Unfortunately, that is a byproduct of a rapidly evolving field. When the ARASENS study started enrolling patients, Docetaxel and ADT was considered the standard of care treatment.

How do we determine which patients get triplet therapy with darolutamide, docetaxel, and ADT vs an AR inhibitor and ADT?

This is controversial. I consider whether patient has high risk disease such as metastatic prostate cancer to liver, Gleason 9 or 10, or high risk prostate adenocarcinoma variants such as somatic gene mutations such as p53, RB1, or PTEN, these mutations portend an aggressive cancer, so these patients should be treated aggressively. I also consider the high volume disease definition from CHAARTED (presense of 4 or more bone lesions with 1 beyond the axial skeleton). For patients with low-volume disease, although triplet therapy is effective, we should consider an AR inhibitor like apalutamide or enzalutamide, with ADT. More data will be coming out in future ASCO meetings on low risk and low volume disease for ARASENS.

What unmet needs remain in mHSPC?

[Precision medicine is] emerging in prostate cancer. PARP inhibitors for patients with BRCA2 or BRCA1mutations are effective in mCRPC. Now, these studies are moving in the mHSPC space. These studies demonstrate that metastatic prostate adenocarcinomas are a heterogenous disease and we should consider their germline and somatic mutations for the most effective treatments. Therefore, [All patients] with mHSPC or newly diagnosed prostate cancer need to have a complete somatic and germline genetic testing done. If they have a somatic or germline mutation, they should be considered for a clinical trial in the metastatic hormone sensitive space. In terms of the specific mutations, they are not all equal, I may be looking for well known genes such as the BRCA2 and BRCA1 mutations for known efficacy for current medications, however there are other gene mutations that are emerging such as PALB2.

Will patients with mHSPC [with BRCA2 and BRCA1 mutations] benefit more [from PARP inhibitors] as an earlier line of treatment? These studies will mature in the next 3-4 years so we should have some more clarity. 

Additionally, radiotheranostics is rapidly emerging in prostate cancer. The clinical study that became the tipping point was the VISION study for patients with metatatic castrate resistant prostate cancer. Our team at Norton Cancer Institute was one of the highest enrollers in the US for this study, and I was very fortunate to be the principal investigator at our site for the [phase 3] VISION study [NCT03511664], which showed that when patients with mCRPC progressed on a taxane and an AR inhibitor, Lutetium 177 [177Lu] PSMA-617 [177Lu-PSMA-617] was very effective in the third line. This medication is rapidly [moving into] earlier lines of treatment. There were news reports in December 2022 that this medication met its primary endpoint for progression-free survival in patients treated after androgen pathway inhibitor and before taxane chemotherapy. This data will be released in a future meeting in 2023. Other studies [are investigating] 177Lu-PSMA-617 with an AR inhibitor in the first line for mCRPC and 177Lu-PSMA-617 plus other theragnostic radioligand treatments in mHSPC.

For the general medical oncologists, we need test[s] to know what medications may work before we prescribe this medication. PSMA PET scan is that biomarker. This was demonstrated in the the TheraP study. The TheraP study [NCT03392428], presented at the [2022 ASCO Annual Meeting], was a phase 2 Australian study that randomized patients to cabazitaxel vs 177Lu-PSMA-617. Study found that patients with a [maximum standardized uptake value (SUVmax)] over 10 tended to benefit best from 177Lu-PSMA-617. [Newly diagnosed patients with metastatic prostate cancer should receive] PSMA PET and genomic and somatic testing. If they have a BRCA2 or BRCA1 mutation, I would give a [PARP inhibitor] with androgen pathway inhibitor in the frontline setting for mCRPC based on the PROpel and Talapro-2 studies released at ASCO GU 2023. Also, if they have a high SUVmax over 10, perhaps [they can receive] 177Lu-PSMA-617 in the 2nd line setting after an AR inhibitor based on the Phase III PSMAFore trial.

This is an exciting time for patients. [We have many] new studies. Across the US, urologists and oncologists are coming together for patient care and doing many clinical studies together.

Regarding the presentation by Jaspreet Grewal, MD, of Norton Cancer Institute, how has the definition of nonmetastatic CRPC changed over time?

Do we treat patients with nonmetastatic CRPC before they have metastatic disease? [The phase 3 ARAMIS study (NCT02200614)] didn’t use the imaging we have today, PSMA PET scans. They used conventional imaging, such as bone scans and CT scans. Some patients may have had metastatic disease that [the study did not] pick up.

[ARAMIS investigated] darolutamide vs placebo for patients with nonmetastatic CRPC, defined as having a [prostate specific antigen (PSA)] doubling time of less than 10 months. Darolutamide [provided an OS] benefit. The [investigators] then did a follow-up using the addendum of a [definitive] doubling time of 6 months or less. ARAMIS was groundbreaking. However, in 2023, with the advent of the PSMA PET scan, how many of these patients truly had nonmetastatic CRPC?

Based on the presentation by Zin W. Myint,MD, of the University of Kentucky Markey Cancer Center in Lexington, how do patients’ mutation statuses affect the efficacy of PARP inhibitorsin mCRPC?

One preliminary work [investigated olaparib in] patients withBRCA1 or BRCA1 mutations who are post-chemotherapy, post-taxane, and post–AR inhibitor. Olaparib [(Lynparza) provided] great progression-free survival[PFS] and radiographic PFS[rPFS].

Additionally, in the [phase 3] PROpel study [NCT03732820], the arms were abiraterone acetate with prednisone and ADT in patients with mCRPC vs olaparib with abiraterone acetate and ADT. This trial was designed for an unselected patient population. It’s still accruing data. However, for unselected patients, there were rPFS and PFS benefits. An update from the [2022 ESMO Congress] investigating the BRCA2 and BRCA1-mutated population showed a profound separation of the curves.

However, in a similar study, the [phase 3] MAGNITUDE trial [NCT03748641], which used a different PARP inhibitor, niraparib [Zejula], with ADT for an unselected patient population, there wasn’t an rPFS separation. This caused much confusion in the GU community. Olaparib is a good PARP inhibitor, butniraparib may not have shown [an rPFS] difference.

The phase 3 TALAPRO-2 trial (NCT03395197), findings from which will be released at the 2023 Genitourinary Cancers Symposium, [investigated] talazoparib [Talzenna]. It will be interesting to see whether there is an rPFS improvement in the unselected population.

Then the question becomes: How is this possible? If patients do not have BRCA1 or BRCA2 mutations and are given a PARP inhibitor, how could that create a response? PARP inhibitors increase AR receptors’ [ability to] bind with AR inhibitors, increasing the efficacy [of AR inhibitors]. Also, some AR inhibitors like abiraterone acetate, apalutamide, and enzalutamide create a BRCA-like environment where PARP inhibitors are more effective.

We [need more research], but the bottom line is, PARP inhibitors with abiraterone acetate tend to be an effective treatment for patients with mCRPC with BRCA2 or BRCA1 mutations. The question becomes: Is this for all-comers? TALAPRO-2 will resolve some of these questions.

Regarding the presentation by Vikas Kumar Singh, MD, of Baptist Health in Louisville, Kentucky,what frontline therapies are available or under investigation for metastatic urothelial cancer?

In first-line bladder cancer treatment, we have some clarity. Based on the [phase 3] JAVELIN Bladder 100 study [NCT02603432], all patients should be considered for a platinum doublet, like cisplatin/gemcitabine, carboplatin/gemcitabine if they’re cisplatin ineligible, or, for some young patients with aggressive cancer, [some providers] in leading academic centers use dose-dense MVAC[methotrexate, vinblastine, doxorubicin (Adriamycin], and cisplatin]. These are all in category 1 of the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. After patients get platinum, [they should receive] maintenance avelumab [Bavencio], a category 1 treatment.

New data are coming out for the platinum-ineligible patients. [In cohort K of the phase 1/2] EV-103 study [(NCT03288545), patients received] frontline enfortumab vedotin-ejfv [Padcev], an ADC, with pembrolizumab [Keytruda]. Data from the 2022 ESMO Congress showed a 64.5% response rate. We don’t have OS data yet. If this combination gets approved, should GU oncologists consider it for platinum-ineligible patients in the first line instead of a platinum doublet with avelumab? 

Based on the presentation by Petros Grivas, MD, PhD, of Fred Hutchinson Cancer Center in Seattle, Washington, what later-line treatments may arise for metastatic urothelial cancer?

There are new data regarding molecular testing and circulating tumor DNA for patients with stage II bladder cancers. However, in the metastatic setting, if patients have progressed on a platinum doublet with avelumab, we need precision medicine. We need to check the next-generation sequencing for FGFR2 or FGFR3 alterations. If a patient has 1 of those, we need to consider the targeted medication erdafitinib [Balversa]. If they don’t have an FGFR2 or FGFR3 mutation, enfortumab vedotin is very effective.

Other ADCs like sacituzumab govitecan-hziy [(Trodelvy) is] very effective for patients. This medication is my preference for patients with with[tough-to-treat] peripheral neuropathy. In patients who receive cisplatin and gemcitabine, 1 of the main AEs is peripheral neuropathy, which is also an AE [seen in] up to 49% of the patients [who receive enfortumab vedotin]. Patients with grade 3 peripheral neuropathy can’t [receive] enfortumab vedotin.

Dr Grivas will present our research data [on] pembrolizumab plus sacituzumab govitecan at the 2023 Genitourinary Cancers Symposium. [The presentation is titled,] "Primary analysis of TROPHY-U-01 cohort 3, a phase 2 study of sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) that progressed after platinum (PT)-based therapy."

Combinations are where [the field is] moving, either enfortumab vedotin with pembrolizumab in the front line, or sacituzumab govitecan with pembrolizumab in subsequent lines.

Regarding the presentation by Rohit Kumar, MD, of the University of Louisville in Kentucky, what frontline combinations are available in RCC?

In metastatic clear cell RCC, we have options. We can consider a dual checkpoint inhibitor combination, nivolumab [Opdivo] and ipilimumab [Yervoy], based on the [phase 3] CheckMate 214 study [NCT02231749]. If there’s a response, we continue with maintenance nivolumab. A downside of nivolumab/ipilimumab is, if a patient doesn’t respond to immunotherapy, that’s 3 months [during which] the cancer can progress. 1 out of 5 patients do not respond to dual check point inhibitors. If they are weak with very poor performance status, some patients may not get to a second-line treatment if you pick the wrong regimen.

It’s important to analyze patients. Are they symptomatic? If so, we should consider immunotherapy with a TKI, [of which we have] 3 options. One is pembrolizumab with axitinib [Inlyta], based on the [phase 3] KEYNOTE-426 trial [NCT02853331]. There are strong data with that combination. If you want to get a patient’s cancer under control with a dual mechanism of action, you get tumor shrinkage [with pembrolizumab plus axitinib].

We also have nivolumab with cabozantinib [Cabometyx] based on the [phase 3] CheckMate 9ER study [NCT03141177]. This regimen, which Toni Choueiri, MD, [of Dana-Farber Cancer Institute in Boston, Massachusetts] presented at the 2022 Genitourinary Cancers Symposium, [provides a]quality of life benefit. Cabozantinib 40 mg is well tolerated. Also, building on the data from the [phase 2] CABOSUN study [NCT01835158], patients with metastatic cancer to the bone responsed very well to Cabozantinib. Therefore for patients with high metastatic bone cancer volume, I consider cabozantinib with nivolumab.

The third option is from the [phase 3] CLEAR study [NCT02811861], which was presented at the 2022 Genitourinary Cancers Symposium by Robert J. Motzer, MD, [of Memorial Sloan Kettering Cancer Center in New York, New York]. CLEAR [investigated] lenvatinib [Lenvima], another TKI, with pembrolizumab. This regimen with lenvatinib at 20 mg provides the highest tumor shrinkage, with a high response rate. Patients had a 71.0% overall response rate with a 16.1% complete response rate. This combination is the most impressive because it has the best response and complete response rate. Therefore, I consider this my main option for fit patients with very high cancer volume. However, I am mindful the toxicity is much higher. This can be easily managed by lowering the lenvatinib right away.

Based on the presentation by Brian Rini, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, how will biomarkers help guide later-line RCC treatment?

[We have a] conundrum of whether we should give nivolumab/ipilimumab or an immunotherapy/TKI [combination]. The [phase 2] OPTIC RCC study [NCT05361720] hypothesized that gene expression clusters, which characterize the tumor biology of each patient, can help us select the best frontline therapy using either an immunotherapy/immunotherapy or immunotherapy/TKI regimen.

Clusters 1 and 2 tend to be TKI-driven. Clusters 4, 5, and 7 may be more immunogenic, ie, may respond better to ipilimumab and nivolumab. When this study progresses, we may have a biomarker [that can help us decide between] nivolumab/ipilimumab in the front line or an immune checkpoint inhibitor with a TKI.

What is your main message for colleagues?

Great data will come out of the 2023 Genitourinary Cancers Symposium. It’s an honor and a privilege to be part of the GU oncology community, which is a microcosm of all the great things in oncology. We have immunotherapy; antibody drug conjugates, circulating tumor DNA, precision oncology treatments with somatic mutations like FGFR3; genetic testing and germline testing like BRCA1 and BRCA2; emerging data with CAR T cells in prostate cancer and in renal cell cancer like they are doing at they City of Hope [in Duarte, California]; and bispecific antibody T-cell engagers for patients with metastatic prostate cancer at Norton Cancer Institute. GU oncologists are very fortunate to be in this rapid evolving and changing field that is improving care for our patients.

Editor's note: This interview was conducted prior to the 2023 Genitourinary Cancers Symposium.

References

1. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115
2. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488