New combinations promote individualized care in bladder and prostate cancer

Experimental 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 therapeutic avenues, according to Alicia Morgans , MD, MPH.

“Keep up with [advances in these fields] it requires ongoing learning and reflection about what therapies are available, what combinations we use them in, when we use them, and how we use them in which patients,” Morgans said in an interview with OncLive® following a OncLive® State of the Science Summit™ (SOSS) on bladder and prostate cancer, which he chaired.

In the interview, Morgans shared key insights from the meeting, including the evolving role of ADT in metastatic hormone-sensitive prostate cancer (mHSPC), combinations of investigational immunotherapy in urothelial cancer, and how antibody conjugates -Drug (ADC) 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 study (NCT03511664). Results demonstrated an imaging-based median 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 regimens of taxanes.1 Morgans discussed next steps to investigate this agent in mHSPC and mCRPC. Regarding urothelial cancer, he explained the rationale for evaluating ADCs, such as enfortumab vedotin-ejfv (Padcev), plus pembrolizumab, a regimen that yielded 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 Phase 1/2 study EV-103 (NCT03288545).2

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

OncLive®: Treatment intensification has demonstrated improved survival in clinical trials in mHSPC, but what does adopting this strategy look like in the real-world context?

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

We must combine ADT with [other agents]. [Most patients] can reap those benefits. Because we are undertreating these patients, we must make a conscious effort to overcome the barriers we face that compel us to undertreat those patients in order to do better.

What therapies and agents have propelled the mHSPC landscape forward?

There are multiple inhibitors of AR signaling that we can use in conjunction with ADT to improve survival and maintain or improve quality of life. These 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. These options also give us an improved operating system and maintained QOL.

Which mHSPC studies are important to watch?

One area of ​​interest is radiopharmaceutical use. The [phase 3] PSMA addition study [NCT04720157] is combining ADT and 177Lu-PSMA-617 with AR signaling inhibitors to see if that triplet combination is better than ADT and just one AR signaling inhibitor. [We’re beginning to] usage 177Lu-PSMA-617 [as a] SOC. Having the opportunity to move that agent from advanced or mCRPC to mHSPC is both exciting and promising. This is a relatively well tolerated agent for most patients and will likely still be well tolerated in combination with a single AR inhibitor. This study is one of the most anticipated of all ongoing mHSPC studies.

What advances do you hope to see in mHSPC treatment?

At mHSPC, I am interested in seeing what further combinations we can develop and use in this context and how we can better understand which patients can benefit most from which treatments. Currently, we are using crude assessments such as the number of metastatic sites to direct our treatment paradigm. If we could use [information] like genomics to understand, from a disease biology perspective, what treatments are needed for an individual patient, we could maximize our treatments when needed and minimize them when we can get good disease control for less. The one size fits all [approach] it will turn into personalization of the treatment.

We also have ground to catch up with regards to implementing the data we already have. Over the next few years, I hope we will continue to improve by providing patients with treatments we already know work before we reduce treatment intensification for some patients and increase it for others.

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

There have been many changes taking place in immunotherapy in advanced disease. Some treatments have been withdrawn. [For instance]atezolizumab [Tecentriq] it is no longer offered for patients with urothelial cancer. Dr. Berg looked at 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 such as ADCs [for greater efficacy].

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

Two ADCs are approved for metastatic urothelial cancer: enfortumab vedotin and sacituzumab govitecan. Both provide a unique mechanism. They are 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 giving chemotherapy. It’s chemotherapy, but we’re delivering it directly to the tumor. This makes its toxicity profile more manageable. These chemotherapies would be too toxic to administer without this antibody mechanism that directly targets cancer cells. This gives us another exciting mechanism of action. These new treatments can be very effective against urothelial carcinoma because they are so targeted and mitigating [toxicities] directly targeting cancer.

We look forward to combinations with agents such as pembrolizumab for both of these drugs because such a combination may provide synergy and allow for greater efficacy and disease control.

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

PARP inhibitors have been an exciting opportunity for patients with mCRPC. Importantly, they were limited to patients with homologous recombination repair mutations and, for 1 agent, only those with BRCA1 And BRCA2 alterations. An interesting detail about potential combinations of PARP inhibitors and inhibitors of AR signaling is that we may be able to use these combinations in mCRPC patients who do not have these alterations. We don’t know if we will eventually get such a wide approval. However, preliminary evidence from the studies presented by Dr. Choudhury suggests that it may be possible, especially since we saw an improvement in radiographic PFS in an all-participant population in one of the studies.

Importantly, we expect to see another study soon reporting to investigate 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 additively and perhaps synergistically.

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

One of the most exciting PSMA-targeted therapies is 177Lu-PSMA-617 for mCRPC patients. Dr. Ravi explained the mechanism and showed data from the Phase 3 trial that led to its approval. He also described the ongoing lawsuits they investigate 177Lu-PSMA-617 in early disease settings and in combination with other agents that could offer a wider opportunity for patients to receive effective treatment from this approach. Finally, it helped us think about which patients would benefit most from treatment with 177Lu-PSMA-617, so we might consider incorporating this into our treatment sequencing in a way that makes sense for an individual [patient].

What is your key message to colleagues?

The therapeutic landscapes for prostate cancer and urothelial carcinoma continue to evolve at a lightning pace. The interventions 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 the Dana-Farber Cancer Institute would you like to highlight?

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

We are also working on drug-sponsored studies, including PSMA Addition and the [phase 3] PSMA before the trial [NCT04689828]2 studies investigating 177Lu-PSMA-617 in advanced prostate cancer to find more opportunities to use this exciting and effective radiopharmaceutical and provide a broader opportunity to a larger population.

References

  1. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N English J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322
  2. Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study LBA73 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 carcinoma (la/mUC) . Ann Oncol. 2022;33(suppl 7):S1441. doi:10.1016/j.annonc.2022.08.079

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