Novel Combinations Promote Individualized Care in Bladder and Prostate Cancer

Alicia Morgans, MD, MPH

Investigational combinations, such as androgen deprivation therapy (ADT) plus Lutetium 177 (¹⁷⁷Lu) PSMA-617 (¹⁷⁷Lu-PSMA-617) and androgen receptor (AR) signaling inhibitors in prostate cancer and sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) in urothelial cancer, may open increasingly specific treatment avenues, according to Alicia Morgans, MD, MPH.

“Keeping on top of [advances in these fields] requires continuous learning and thinking about what therapies are available, in what combinations we use them, when we use them, and how we use them in which patients,” Morgans said in an interview with OncLive^® following an OncLive^® State of the Science Summit™ (SOSS) on bladder and prostate cancer, which she chaired.

In the interview, Morgans shared key insights from the meeting, including the evolving role of ADT in metastatic hormone-sensitive prostate cancer (mHSPC), investigational immunotherapy combinations in urothelial cancer, and how antibody-drug conjugates (ADCs) provide a unique means of delivering toxic agents directly to tumors.

¹⁷⁷Lu-PSMA-617 was previously studied in metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 VISION trial (NCT03511664). The results demonstrated a median imaging-based progression-free survival (PFS) of 8.7 months and a median overall survival (OS) of 15.3 months with vs ¹⁷⁷Lu-PSMA-617 3.4 months and 11.3 months, respectively, with standard of care (SOC) in prostate-specific membrane antigen (PSMA)-positive patients previously treated with at least one AR inhibitor and one or two taxane regimens.¹ Morgans discussed the next steps for investigating this agent in mHSPC and mCRPC. Regarding urothelial cancer, she explained the rationale for evaluating ADCs, such as enfortumab vedotin-ejfv (Padcev), plus pembrolizumab, a regimen that produced a confirmed overall response rate of 64.5% vs 45.2% with enfortumab vedotin monotherapy as first-line therapy in cisplatin-ineligible patients with locally advanced or metastatic disease (cohort K) in the phase 1/2 EV-103 study (NCT03288545).²

Morgans is the medical director of the Survivorship Program at Dana-Farber Cancer Institute and a member of the Faculty of Medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive^®: Treatment intensification has shown improved survival in clinical trials in mHSPC, but what does this strategy’s uptake look like in the real-world setting?

Morgans: I spoke about mHSPC and the need to intensify treatment for most of these patients. Although as a field we still use ADT alone in around half our patients, ADT plus [another agent], such as an AR signaling inhibitor or in a triplet with docetaxel and abiraterone acetate [Zytiga] or darolutamide [Nubeqa], is associated with improved survival and disease control, as well as improved and maintained quality of life [QOL].

We need to combine ADT with [other agents]. [Most patients] can reap those benefits. Because we’re undertreating these patients, we need to make a conscious effort to overcome the barriers facing us and causing us to undertreat those patients to do better.

What therapies and agents have pushed the mHSPC landscape forward?

There are multiple AR signaling inhibitors that we can use in combination with ADT to improve survival and maintain or improve QOL. Those include abiraterone acetate plus prednisone, enzalutamide [Xtandi], and apalutamide [Erleada].

Another avenue is the triplet combination we use for patients with de novo metastatic and high-volume metastatic disease: ADT, 6 cycles of docetaxel, and darolutamide or abiraterone acetate, which are continued until disease progression. Those options also give us improved OS and maintained QOL.

What mHSPC trials are important to keep an eye on?

One area of interest is radiopharmaceutical use. The [phase 3] PSMAddition study [NCT04720157] is combining ADT and ¹⁷⁷Lu-PSMA-617 with AR signaling inhibitors to see if that triplet combination is better than ADT and an AR signaling inhibitor alone. [We’re beginning to] use ¹⁷⁷Lu-PSMA-617 [as a] SOC. Having the opportunity to move that agent from advanced or mCRPC into mHSPC is exciting and hopeful. That’s a relatively well tolerated agent for most patients and will probably still be well tolerated in combination with an AR singling inhibitor. That study is 1 of the most highly anticipated of all the mHSPC trials we have going on.

What advances are you hoping to see in mHSPC treatment?

In mHSPC, I’m interested to see what further combinations we may develop and use in this setting and what ways we can better understand which patients may benefit most from which treatments. Currently, we’re using crude assessments like number of metastatic sites to direct our treatment paradigm. If we could use [information] like genomics to understand, from a disease biology standpoint, which treatments are necessary for an individual patient, we could maximize our treatments when necessary and minimize them when we can get good disease control with less. The one-size-fits-all [approach] will transform into treatment personalization.

Additionally, we have ground to make up regarding implementing the data we already have. In the next few years, I hope we will continue to improve by giving patients treatments that we already know work before we pare down treatment intensification for some patients and increase it for others.

Stephanie Berg, DO, of Dana-Farber Cancer Institute, discussed immunotherapy in metastatic urothelial cancer. How has the withdrawn indication for atezolizumab (Tecentriq) affected immunotherapy development?

There’s been much change going on in immunotherapy in advanced disease. Some treatments have been withdrawn. [For instance], atezolizumab [Tecentriq] is no longer offered for patients with urothelial carcinoma. Dr Berg reviewed some data and some areas where we still have opportunities and gave us a forward-looking understanding of where we might combine immunotherapy for urothelial carcinoma with agents like ADCs [for greater efficacy].

Bradley McGregor, MD, of Dana-Farber Cancer Institute, talked about ADCs in metastatic urothelial cancer. Which agents could make for the best combination partner based on the mechanism of action of these drugs?

Two ADCs are approved for metastatic urothelial carcinoma: enfortumab vedotin and sacituzumab govitecan. Both provide a unique mechanism. They’re both targeted but with different ligands that allow us to deliver toxic treatments directly to the cancer.

Dr McGregor encouraged us to think of this as delivering chemotherapy. It is chemotherapy, but we’re delivering it right to the tumor. That makes its toxicity profile more manageable. These chemotherapies would be too toxic to deliver without this mechanism of the antibody targeting the cancer cells directly. That gives us another exciting mechanism of action. These new treatments can be highly effective against urothelial carcinoma because they’re so targeted and they mitigate [toxicities] by directly targeting the cancer.

We are also looking forward to combinations with agents like pembrolizumab for both these drugs because that combination may provide synergy and allow more efficacy and disease control.

Regarding the presentation given by Atish Choudhury, MD, PhD, of Dana-Farber Cancer Institute, what is exciting about potentially be able to combine PARP inhibitors with AR inhibitors in mCRPC?

PARP inhibitors have been an exciting opportunity for patients with mCRPC. Importantly, they have been limited to patients with homologous recombination repair mutations, and for 1 agent, only those with BRCA1 and BRCA2 alterations. One exciting detail about potential combinations of PARP inhibitors and AR signaling inhibitors is that we might be able to use these combinations in patients with mCRPC who don’t have these alterations. We don’t know whether we will ultimately have that broad of an approval. However, preliminary evidence from the studies presented by Dr Choudhury suggests that may be possible, especially because we saw an improvement in radiographic PFS in an all-comer population in 1 of the trials.

Importantly, we are expecting to see another trial reporting out soon investigating a separate combination of a PARP inhibitor and an AR signaling inhibitor. We will have more evidence to help us understand how these agents might work together in an additive fashion and perhaps in a synergistic way.

Praful Ravi, MB, BChir, MRPC, of Dana-Farber Cancer Institute, discussed PSMA-targeted therapies. What does the future hold for ¹⁷⁷Lu-PSMA-617?

One of the most exciting PSMA-targeted therapies is ¹⁷⁷Lu-PSMA-617 for patients with mCRPC. Dr Ravi explained the mechanism and showed data from the phase 3 trial that led to its approval. He also described ongoing trials investigating ¹⁷⁷Lu-PSMA-617 in earlier disease settings and in combination with other agents that might give a broader opportunity for patients to receive effective treatment from this approach. Finally, he helped us think through which patients may benefit most from treatment with ¹⁷⁷Lu-PSMA-617, so we could consider incorporating this into our treatment sequencing in a way that makes sense for an individual [patient].

What is your key message for colleagues?

The treatment landscapes for prostate cancer and urothelial carcinoma continue to evolve at a lightning pace. The talks that were presented at the SOSS [reminded us to stay] on the edge of our seats as we learn about the exciting new therapies available.

What ongoing research at Dana-Farber Cancer Institute would you like to highlight?

Dana-Farber Cancer Institute is involved in ongoing research trials for many of the agents that were discussed in this SOSS, including exciting investigator-initiated trials. The [phase 1] DAD trial [NCT04724018] is combining sacituzumab govitecan and enfortumab vedotin in patients with advanced urothelial carcinoma, providing the potential opportunity to use both those mechanisms of action to work against that cancer.

We are also working on pharmaceutical-sponsored trials, including PSMAddition and the [phase 3] PSMAfore trial [NCT04689828], 2 studies investigating ¹⁷⁷Lu-PSMA-617 in advanced prostate cancer to find other opportunities to use this exciting and effective radiopharmaceutical and give a broader opportunity for a larger population.

Editor's Note: Dr Morgans has consulting positions with AstraZeneca, Astellas, AAA, Bayer, Dendreon, Exelixis, Janssen, Myovant, Myriad Genetics, Novartis, Pfizer, Sanofi, and Telix; and has conducted research for Astellas, Bayer, Dendreon, Janssen, Myovant, Pfizer, Sanofi, and SeaGen.

References

1. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322
2. Rosenberg JE, Milowsky M, Ramamurthy C, et al. LBA73 study EV-103 cohort K: antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Ann Oncol. 2022;33(suppl 7):S1441. doi:10.1016/j.annonc.2022.08.079