Individualized Treatment Selection and Sequencing Enhances Bladder and Prostate Cancer Management

Daniel S. Childs, MD

Treatment evolutions involving biomarker identification, PARP inhibitor application, and the development of a host of PSMA-directed radiopharmaceuticals may augment the future of the prostate cancer armamentarium, according to Daniel (Dan) S. Childs, MD. Additionally, antibody-drug conjugates (ADCs) have secured a place in the metastatic urothelial cancer treatment paradigm.

During an OncLive^® Institutional Perspectives in Cancer webinar on prostate and bladder cancer, Childs and colleagues spotlighted future innovations in the management of metastatic hormone-sensitive prostate cancer (mHSPC), treatment sequencing for metastatic urothelial carcinoma, key data with PARP inhibitor combinations in metastatic castration-resistant prostate cancer (mCRPC), and the wave of advances on the horizon with PSMA radiopharmaceuticals.

“With the success of triplet [therapies], there is little, if any, role for androgen deprivation therapy [ADT] plus docetaxel without concurrent use of an androgen receptor pathway inhibitor [ARPI],” Childs said of the mHSPC treatment landscape during his presentation.

Childs, who chaired the event, is a senior associate consultant at Mayo Clinic Comprehensive Cancer Center and Mayo Clinic Alix School of Medicine in Rochester, Minnesota.

Childs was joined by his colleagues:

• Lance C. Pagliaro, MD, professor of oncology, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota
• Alan H Bryce, MD, professor of medicine, consultant, chair, Division of Hematology and Medical Oncology, Department of Internal Medicine, acting director, Arizona Cancers Programs, site director, Mayo Clinic Comprehensive Cancer Center, Phoenix, Arizona
• Oliver Sartor, MD, director of Radiopharmaceutical Trials, Mayo Clinic, Rochester, Minnesota

Below, Childs, Pagliaro, Bryce, and Sartor summarize key points from their presentations.

Updates in mHSPC

Childs: Not every patient with mHSPC needs chemotherapy, but if chemotherapy is selected, I recommend using abiraterone acetate [Zytiga] or darolutamide [Nubeqa] in combination [with the chemotherapy]. There remain unanswered questions about triplets vs doublets that include ADT and an ARPI. Prospective clinical trials [to answer these questions] do not yet exist.

What are the future directions? We talked about chemotherapy-containing triplets. Something that’s exciting is radiopharmaceuticals moving into earlier lines of therapy. The PSMAddition trial [NCT04720157] has completed accrual. That is a phase 3 clinical trial comparing ADT plus an ARPI with a triplet containing lutetium Lu 177 vipivotide tetraxetan.

We talked about [treatment] intensification. It’s also important to talk about the other end of the spectrum. We see so many patients with an exceptional response to treatment, and it would be wonderful if we had biomarkers that allowed us to de-escalate therapy. The Alliance [group] has a [phase 2] trial going on right now called A-DREAM [NCT05241860], which is investigating the interruption of hormone therapies among patients who respond exceptionally well with hormone treatment. I’m excited to see new biomarkers explored other than the timing and volume of metastatic disease.

When we see patients with mHSPC, many of us get both germline and somatic testing. SPOP is a mutation that is frequently encountered, and it’s emerged as a predictive biomarker of response with ARPIs but not with chemotherapy. Perhaps there are other molecular markers that could be used to inform treatment decisions in the hormone-sensitive setting.

People like Alicia Morgans, MD, MPH, [of Dana-Farber Cancer Institute in Boston, Massachusetts], are thinking about risk in innovative ways. [Dr Morgans] has used patient-reported outcomes to understand which patients might benefit most from chemotherapy. In an interesting retrospective analysis of data from the [phase 3] CHAARTED [NCT00309985], she found that patients with the poorest quality of life scores benefitted from ADT and docetaxel compared with ADT monotherapy, regardless of their disease volume.

Lastly, there are more and more biomarker-informed trials in the hormone-sensitive setting. I highlighted 2. The [phase 3] AMPLITUDE trial [NCT04497844] is evaluating PARP inhibitors for patients with homologous recombination repair [HRR] alterations, and CAPItello-281 [NCT04493853] is a [phase 3] clinical trial investigating an AKT inhibitor in patients with PTEN loss. It’s an exciting time in prostate cancer.

Updates in Metastatic Urothelial Carcinoma

Pagliaro: We have the following sequencing of therapies for many patients with metastatic urothelial carcinoma. Start with a platinum-based chemotherapy if they’re platinum eligible. If they have stable disease or better, go on to maintenance avelumab [Bavencio]. If they have progressive disease, perhaps go on to avelumab or another checkpoint inhibitor. If they’re platinum ineligible, [they may receive] a checkpoint inhibitor in the first line. After checkpoint inhibitor therapy, patients can receive second- or third-line treatment with an ADC.

In the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, enfortumab vedotin-ejfv [Padcev] is the preferred second- or third-line systemic therapy after a checkpoint inhibitor based on level 1 evidence from the [phase 1/2] EV-103 trial [NCT03288545], which randomly assigned patients to enfortumab vedotin or physician’s choice of single-agent chemotherapy. Sacituzumab govitecan-hziy [Trodelvy], on the other hand, has an “other recommended” designation based on phase 2 evidence from the TROPHY-U-01 trial [NCT03547973]. With the availability of enfortumab vedotin and sacituzumab govitecan, we have 2 possible sequences of systemic therapy for patients depending on whether they are eligible for gemcitabine/cisplatin or gemcitabine/carboplatin vs those who are platinum ineligible.

After immune checkpoint inhibitor therapy, patients can receive an ADC, preferably enfortumab vedotin, followed by sacituzumab govitecan. However, for patients who experience peripheral neuropathy secondary to cisplatin chemotherapy, or [patients] who have preexisting peripheral neuropathy, enfortumab vedotin may not be tolerable. Enfortumab vedotin is associated with peripheral neuropathy, skin rash, and elevated blood glucose. In these cases, one can start with sacituzumab govitecan, which may be better tolerated, possibly followed by enfortumab vedotin, depending on patient tolerance.

PARP Inhibitors for mCRPC

Bryce: [In the phase 3 PROfound trial (NCT02987543)], the radiographic progression-free survival [(rPFS) with olaparib (Lynparza)] in cohort A was good, with a hazard ratio [HR] of 0.34 and a median rPFS of 7.39 months vs 3.55 months with the ARPI [alone]. Also, [we saw] nice overall survival [OS] results, with an HR of 0.69, [which was] statistically significant. [There was a] 19.1-month median OS [with olaparib] vs 14.7 months with androgen receptor–directed therapy.

Considering the primary end point [of the phase 3 PROpel trial (NCT03732820)] in the patients with HRR-mutant disease, there were strong rPFS results [with abiraterone acetate plus olaparib], with an HR of 0.50. This is statistically significant. The median rPFS was not reached in the combination arm vs 13.9 months in the abiraterone acetate/[placebo] arm. However, some of the controversy and many of the conversations around these combinations come up regarding the population of patients with non-mutant disease. [In that population], there was a statistically meaningful and significant [rPFS] result. The HR was 0.76, and there was separation of these curves, perhaps validating the preclinical data.

The OS data are strongly positive for the population with HRR-aberrant disease, with an HR of 0.66. However, disappointingly, we don’t see this same strong signal in the [population without HRR mutations]. Now, we have that oncology conundrum of PFS results that look good and don’t translate into an OS [benefit]. What do we do with data like those?

The primary end point [in the phase 3 MAGNITUDE trial (NCT03748641)] in the population of patients with HRR-mutant disease was positive in favor of the experimental arm, so niraparib [Zejula] added to abiraterone acetate and ADT improved rPFS [vs placebo plus abiraterone acetate], with an HR of 0.73. If you look specifically at the population of patients with BRCA1/2 mutations, the HR is stronger, at 0.53, with an improvement in OS of almost 6 months.

2023 Updates in PSMA Radiopharmaceuticals

Sartor: Everyone knows about PSMA-617 [Pluvicto] because that’s FDA approved. I thought it would be interesting for people to see the broad range of molecules that are now under development for binding PSMA and delivering targeted radiotherapy. There are antibodies [such as] J591, TLX592, and Bay2315487. These are antibodies that are now in clinical development.

Then, there is a whole series of small molecules beyond PSMA-617, including ones such as PSMA I&T, PNT 2001, PSMA-R2, NG001, ADVC001, ITM-22, “092”, PSMA-EB, and more. One of the things to be aware of is the tsunami that is moving forward to be able to attack PSMA with various molecules, each of which have advantages and disadvantages.