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 carcinoma, may open up increasingly specific treatment options, according to Alicia Morgans, MD, MPH.
“During [advances in these fields] it 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 art OncLive® State of Science Summit™ (SOSS) on bladder and prostate cancer, which she chaired.
In an interview, Morgans shared key insights from the meeting, including the growing role of ADT in metastatic hormone-sensitive prostate cancer (mHSPC), immunotherapy combinations being investigated in urothelial carcinoma, and how antibody-drug conjugates (ADCs) provide a unique way to deliver toxicants 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 showed a 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 taxane regimens.1 Morgans discussed the next steps for investigating this agent in mHSPC and mCRPC. For urothelial carcinoma, 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% versus 45.2% with with enfortumab vedotin monotherapy as first-line therapy in cisplatin-naïve 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 the 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 mHSPC clinical trials, but what does acceptance of this strategy look like in the real-world setting?
The Morgans: I talked about mHSPC and the need to intensify the treatment of most of these patients. Although as a field we still use ADT alone in about half of 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]it is associated with improved survival and disease control, as well as improved and sustained quality of life [QOL].
We need to combine ADT with [other agents]. [Most patients] can take advantage of these advantages. Because we are undertreating these patients, we must make a conscious effort to overcome the obstacles we face that cause us to undertreat these patients in order to do better.
What therapies and agents have pushed the mHSPC landscape forward?
There are multiple inhibitors of AR signaling that we can use in combination with ADT to improve survival and maintain or improve quality of life. These include abiraterone acetate plus prednisone, enzalutamide [Xtandi]and apalutamide [Erleada].
The second route is a triplet combination that we use for patients with de novo metastatic disease 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 improved OS and maintained QOL.
Which mHSPC tests are important to look out for?
One area of interest is the use of radiopharmaceuticals. The [phase 3] PSM Additional study [NCT04720157] combines ADT and 177Lu-PSMA-617 with AR signaling inhibitors to see if that triplet combination is better than ADT and AR signaling inhibitors alone. [We’re beginning to] use 177Lu-PSMA-617 [as a] SOC. Having the opportunity to move that agent from advanced or mCRPC to mHSPC is exciting and hopeful. It is an agent that is relatively well tolerated by most patients and is likely to continue to be well tolerated in combination with an AR release inhibitor. This study is one of the most anticipated of all the mHSPC studies we are conducting.
What kind of progress do you hope to see in the treatment of mHSPC?
In mHSPC, I am interested in what further combinations we can develop and use in this setting and in what ways we can better understand which patients may benefit most from which treatments. We currently use crude estimates such as the number of metastatic sites to guide our treatment paradigm. If we could use [information] like genomics to understand, from a disease biology point of view, what treatments are needed for an individual patient, we could maximize our treatments when needed and minimize them when we can achieve good disease control with less. One size fits all [approach] it will translate into personalization of treatment.
Additionally, we have ground to catch up on implementing the data we already have. In the next few years, I hope that we will continue to improve by giving patients treatments that we already know work before reducing treatment intensification for some patients and increasing it for others.
Stephanie Berg, DO, of the Dana-Farber Cancer Institute, discussed immunotherapy in metastatic urothelial carcinoma. How did the withdrawn indication for atezolizumab (Tecentriq) affect the development of immunotherapy?
Many changes are occurring in the immunotherapy of advanced disease. Some treatments have been withdrawn. [For instance]atezolizumab [Tecentriq] it is no longer offered for patients with urothelial carcinoma. dr. Berg reviewed some of the data and some of the areas where we still have options 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, Dana-Farber Cancer Institute, discussed ADCs in metastatic urothelial carcinoma. Which agents could be the best combination partner based on the mechanism of action of these drugs?
Two ADCs have been approved for metastatic urothelial carcinoma: enfortumab vedotin and sacituzumab govitecan. Both provide a unique mechanism. Both are 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 deliver it right to the tumor. This makes its toxicity profile more manageable. These chemotherapies would be too toxic to deliver 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 palliative [toxicities] by directly targeting cancer.
We are also looking forward to combinations with agents such as pembrolizumab for both of these drugs as this combination may provide synergy and enable greater efficacy and disease control.
Regarding the presentation given by Atish Choudhury, MD, PhD, of the Dana-Farber Cancer Institute, what is exciting about the potential possibility of combining PARP inhibitors with AR inhibitors in mCRPC?
PARP inhibitors have been an exciting opportunity for mCRPC patients. Importantly, they are limited to patients with homologous recombination repair mutations and, for 1 agent, only to those with BRCA1 and BRCA2 alterations. One exciting detail about possible combinations of PARP inhibitors and AR signaling inhibitors is that we could use these combinations in mCRPC patients who do not have these changes. We don’t know if we’ll end up with such broad approval. However, preliminary evidence from studies presented by Dr. Choudhury suggests that this may be possible, particularly because we saw an improvement in radiographic PFS in the all-comer population in one of the trials.
More importantly, we expect to see another trial soon on a separate combination of a PARP inhibitor and an AR signaling inhibitor. We will have more evidence to help us understand how these agents can work together in an additive fashion, and perhaps in a synergistic fashion.
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 therapies targeting PSMA is 177Lu-PSMA-617 for patients with mCRPC. dr. Ravi explained the mechanism and showed the data from the phase 3 trial that led to its approval. He also described the ongoing trials 177Lu-PSMA-617 in earlier disease settings and in combination with other agents may provide a greater opportunity for patients to receive effective treatment with this approach. Finally, it helped us think about which patients might benefit most from treatment 177Lu-PSMA-617, so we might consider incorporating this into our treatment sequence in a way that makes sense for the individual [patient].
What is your key message to colleagues?
The treatment of prostate cancer and urothelial carcinoma continues to develop at lightning speed. Conversations presented at 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 for many of the agents discussed in this SOSS, including exciting investigator-initiated trials. The [phase 1] DAD trial [NCT04724018] combines sacituzumab govitecan and enfortumab vedotin in patients with advanced urothelial carcinoma, providing a potential opportunity to use both mechanisms of action to act against this cancer.
We are also working on drug-sponsored trials, including PSMAddition and [phase 3] PSMAbefore the 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 to a larger population.
- 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
- Rosenberg JE, Milowsky M, Ramamurthy C, et al. LBA73 study EV-103 Cohort K: antitumor activity of enfortumab vedotin (EV) as 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