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In an interview with Targeted Oncology™, Rohan Garje, MD, discussed available therapies, how to assess risks, and manage toxicities for patients with renal cell carcinoma.

Kidney Cancer Awareness Month: Assessing Best Treatment Options in RCC

The phase 1 study of ADXS-504 for the treatment of early prostate cancer is ongoing and new patients with be enrolled to test a higher dose level.

Study of ADXS-504 Monotherapy to Enroll More Patients With Early Prostate Cancer

Results from a phase 3 study show that the continuous maintenance therapy of enzalutamide reduces the risk of disease progression in certain patients with metastatic castration resistant prostate cancer.

Continuous Enzalutamide Proves Beneficial in Previously Treated mCRPC

In a first-in-human trial, a peptide-drug conjugate showed tolerability and antitumor activity in patients with advanced solid tumors. 

CBX-12 Shows Antitumor Activity and Safety in Solid Tumors

Patients with metastatic castration-resistant prostate cancer treated with darolutamide for more than 4 years tolerated well the adverse effects of the drug.

Long-Term Darolutamide Displays Favorable Safety Profile in Patients With mCRPC

Guru P. Sonpavde, MD, a medical oncologist, and the GU Oncology director, Christopher K. Glanz Chair for Bladder Cancer Research, AdventHealth Cancer Institute, provides rationale for the phase 3b STRONG study (NCT03084471) and discusses the early data.

Sonpavde says that durvalumab (Imfinzi), as used in the STRONG study, is an FDA-approved treatment for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The FDA-recommended dose of durvalumab was 10 mg/kg given intravenously over 60 minutes every 2 weeks. In STRONG, investigators increased the dosage of durvalumab to 1,500 mg to determine the safety and efficacy of the higher dose.


 So, the STRONG study was a phase 3B study that examined fixed dose durvalumab. So, we administered durvalumab at 1m500 milligrams, intravenously every 4 weeks in patients with metastatic urothelial carcinoma who progressed on or after platinum-based chemotherapy. So, that is a little bit different than the experience so far. Durvalumab was approved for metastatic urothelial [cancer], which was basically using the 10 milligram per kilogram dose once every 2 weeks.

 The other difference in the STRONG study was that the study allowed both urothelial and non-urothelial carcinoma. Also, in terms of prior therapy, in addition to platinum- based chemotherapy, it allowed other types of chemotherapy. This is why the STRONG study was done, to essentially to look at the safety and toxicity profile of this fixed dose durvalumab, but also look at these other groups of patients that were not studied in the initial studies.


 What was previously presented was a phase 2 trial. It was a large non-randomized phase 2 trial called the 1108 trial, in which there was at a dose of 10 milligrams per kilo, every 2 weeks intravenously, was looked at in patients with metastatic urothelial or predominantly urothelial carcinoma. And based on that study, which showed a response rate in the 15% range, with safety, also demonstrated, led to the approval of the durvalumab in this population, this has been about three years ago now. So, that is the background before [the STRONG] study was launched.

Videos

Guru P. Sonpavde, MD, provides rationale for the phase 3b STRONG study, and discusses the early data.

Background on the STRONG Study of Durvalumab in Urinary Tract Carcinoma

Tracy L. Rose, MD, MPH, an assistant professor of Medicine in the Division of Oncology at the University of North Carolina at Chapel Hill, discussed important and ongoing research in bladder cancer.

Rose states that much of the research in bladder cancer is aimed at improving upon the standard of care which is combination chemotherapy including cisplatin. Improving these combinations has involved administering more doses of chemotherapy and added immune checkpoint inhibitors.

 So we've had a ton of, you know, trying to build on the current standard of cisplatin-based combination chemotherapy. So, you know, the first thing that happened was instead of sort of conventional dose [of] cisplatin, there have been several studies that have come out now with randomized data of what's called dose-dense cisplatin, or dose density. And that's essentially giving chemotherapy more frequently to try to increase dose density and tumor response. And we've seen some good outcomes that look like, you know, these regimens are safe. They're associated with slightly higher pathologic response rates.

 And just last year, at ESMO, there was a presentation that actually 1 of the dose-dense regimens; dose-dense MVAC was associated with a longer progression-free survival than gemcitabine and cisplatin after surgery. Now, they gave different doses of cisplatin between those 2 regimens. So, the jury's still out whether, you know, the same amount of cisplatin really would improve outcomes or not, but it [is] certainly provocative.

 And then there's been several combination studies of, you know, cisplatin-based combination chemotherapy, plus immune checkpoint inhibitors, which have really changed the landscape of metastatic disease. And so those all look safe and relatively consistent across the trials that we're getting pretty good pathologic, downstaging and pathologic, complete response with those combinations. They now need to be tested in the randomized setting to see if we can improve on just chemotherapy alone. And then, in the cisplatin-ineligible group of patients that can't get chemotherapy, how can we improve their outcomes and so there's been a number of studies recently looking at immune checkpoint inhibitors alone, which actually look like they have activity and are now going to be studied randomized against surgery alone. And the enfortumab vedotin [Padcev] is a drug that's being studied extensively now in the neoadjuvant setting, including an exciting abstract that was presented of enfortumab alone given before surgery.

Tracy L. Rose, MD, MPH, discusses ongoing research in bladder cancer that aims to add onto the standard of care and improve patient outcomes. 

Bladder Cancer

Improving Cisplatin-Based Combinations in Bladder Cancer

Tanya Dorff, MD, a medical oncologist, section chief of Genitourinary Disease Program, and associate professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, discusses the introduction of chimeric antigen receptor (CAR) T-cell therapy into the prostate cancer landscape.


Dorff says that bringing CAR T cells to the solid tumor landscape following much success in hematologic malignancies is not easy. The location of a tumor and the heterogeneity of many solid tumors comes with treatment challenges that do not occur in hematologic malignancies.

What is unique with the prostate cancer space is that specific targets do exist that have the potential to help drive the development of CAR T cells for the treatment of prostate cancer.


 This is a technology that's been super successful in hematologic malignancies. But there are certainly challenges in bringing it into solid tumors, and particularly, I would say for prostate cancer because of the differences in the kinds of diseases and where they reside and tumor heterogeneity in solid tumors that you don't see with leukemias and lymphomas.

 But that being said, there are a number of really specific targets that define prostate cancer cells that we can use to produce car T cells. And they've been shown in preclinical models to really be able to find the prostate cancer and destroy it. And so, it's just a question of how to make that translate into clinical trials and what to expect in terms of toxicity. It just looks completely different than hematologic malignancies although, of course, we're learning from the experience in those diseases.

Tanya Dorff, MD,  discusses the introduction of chimeric antigen receptor T-cell therapy into the prostate cancer landscape.

Conference News

Prostate Cancer

Exploring CAR T Cells in Prostate Cancer

Clayton Lau, MD, chief, Division of Urology and Urologic Oncology, director, Prostate Cancer Program, head, Retroperitoneal Surgery, an associate clinical professor, Department of Surgery at the City of Hope Comprehensive Cancer Center, advises primary care physicians and specialists on how to help address the rising prevalence of advanced-stage genitourinary (GU) cancers.

According to a recent interview with Lau, there has been a large number of patients with advanced disease during the COVID-19 pandemic. Much of the problem is related to lack of screening, late screening, and patients not going to the doctor.

Lau believes that providers can be a part of the solution moving forward.

 I think it's important for physicians, you know, specifically primary care doctors or even specialists to tell their patients to or educate the patients to continue the screening. You know, for the GU cancers, certainly for patients that have first view relatives that have prostate cancer, they probably should be screened sooner than traditionally. So, start screening patients at age 40.

 Also, [for] African Americans, certainly consider screening earlier having that conversation. You know, consider screening at 40 or 45, with the PSA, rectal exam and maybe even an MRI to help determine if they have something that's, you know, they need to be biopsied. But it's important for all physicians to that, you know, to have their patients screened for all the GU cancers and other cancers.

Clayton Lau, MD, advises primary care physicians and specialists on how to help address the rising prevalence of advanced-stage genitourinary cancers.










Advice on Addressing Advanced-Stage Diagnosis of GU Cancers During COVID-19

Yousef Zakharia, MD, clinical associate professor of internal medicine at the University of Iowa, Holden Comprehensive Cancer Center, discusses the results of a phase 2 trial (NCT02891161) investigating concurrent durvalumab (Imfinzi) and radiation therapy followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder.

This study enrolled 26 patients and the investigators had efficacy data for 24 patients. This regimen was deemed safe for use in patients and the safety has been presented prior to the efficacy. There were no major dose-limiting toxicities with this combination, according to Zakharia.

In the 24 evaluable patients, there was a disease control rate of 72% at the end of 1 year. After the completion of adjuvant daratumumab, there were 10 complete response, 3 partial responses, 1 patient with stable disease, and 6 patients with progressive disease. Zakharia says the progression-free survival rate was about 70%. The 1-year overall survival probability was 83.8% and the 2-year probability was 76.8%. The median overall survival had not been reached.

Yousef Zakharia, MD, discusses the results of a phase 2 trial investigating concurrent durvalumab and radiation therapy followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder.

Durvalumab Plus Radiation Therapy Demonstrates Efficacy in Bladder Cancer

Thomas Marron, PhD, MD, assistant director of early phase and immunotherapy clinical trial at the Tisch Cancer Institute and assistant professor of medicine at the Icahn School of Medicine at Mount Sinai discusses the need for effective neoadjuvant therapies in hepatocellular carcinoma (HCC).

According to Marron, surgeons at his cancer center perform well over 100 surgeries for HCC a year, but the vast majority of patients have recurrence, most of which is a local or regional occurrence. Vary rarely is the recurrence in the surgery margin. Marron says this means that most of the recurrence is due to micro metastatic disease.

To date, no trials have demonstrated survival advantage of preoperative or post-operative therapy in HCC. However, according to Marron, the neoadjuvant space is growing for many cancer types. Due to the lack of research, HCC is an optimal space for this growth to occur.

According to Marron, incidences of HCC is growing due to both Hepatitis B and non-alcoholic steatohepatitis infections, which are becoming increasingly more common in the United States. As health care providers become more efficient at detecting early stage operable legions, it’s important that surgery become the determining therapy.

Thomas Marron, PhD, MD, discusses the need for effective neoadjuvant therapies in hepatocellular carcinoma.

News

The Need for Novel Neoadjuvant Therapies in HCC

Thomas Hutson, DO, PharmD, director of the Urologic Oncology Program and co-chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center and professor of medicine, Texas A&M College of Medicine, suggests the areas new research for non-clear cell renal cell carcinoma (RCC) should explore.

According to Hutson, the next step in research for non-clear cell RCC should focus on further understanding the pathogenesis for each histologic subtype. While newer generation drugs such as lenvatinib (Lenvima) and everolimus (Zortress) show higher activity than earlier generation drugs, new targeted therapies are needed if the efficacy in non-clear cell RCC is ongoing to rival the efficacy seen in clear cell RCC.

Hutson says that these newer-generation drugs will most likely not be studied in large phase 3 trials as these histologies are rare. It would take years to accrue enough patients for regulatory approval, explains Hutson. The best thing to do, he says, is too keep researching and make the data publicly available to health care providers in order to help them make informed treatment decisions. 

Thomas Hutson, DO, PharmD suggests the areas new research for non-clear cell renal cell carcinoma should explore.

Next Steps in Non-Clear Cell Renal Cell Carcinoma Research 

Historic Level of Progress in First-Line RCC Treatment

Strong Efficacy and Favorable Safety From CLEAR for RCC

Dosing Strategies to Maximize Efficacy in RCC

Considerations for Len-Pembro in Clinical Practice

What’s Next for Advanced RCC?

Robert J. Motzer, MD, provides perspective on recent data from the phase 3 CLEAR trial (Study 307)/KEYNOTE-581 for advanced renal cell carcinoma.

Are Combinations the Answer in Metastatic RCC?

Petros Grivas, MD, PhD, physician, Seattle Cancer Care Alliance; associate professor, Department of Medicine, Division of Oncology, and clinical director, Genitourinary Cancers Program, University of Washington School of Medicine; and associate member, Clinical Research Division, Fred Hutchinson Cancer Center, discusses the phase 3 KEYNOTE-045 trial and the association between gene expression signatures and pembrolizumab (Keytruda) in patients with advanced urothelial cancer.

All the patients receiving pembrolizumab on the KEYNOTE-045 trial appeared to benefit in terms of progression-free survival and overall survival, according to Grivas. There are no biomarkers with clinical utility that can guide selection of which patients should get pembrolizumab or not, based on the data presented the 2020 European Society for Medical Oncology. Therefore, these data show no impact on practice when using pembrolizumab to treat patients with platinum-refractory disease.

Grivas says that the utilization of pembrolizumab based on potential biomarkers needs to be researched further to evaluate the clinical advantage of gene expression signatures. At the moment, patients with platinum-refractory advanced urothelial cancer are all treated able to be treated with pembrolizumab.

Petros Grivas, MD, PhD, discusses the phase 3 KEYNOTE-045 trial and the association between gene expression signatures and pembrolizumab in patients with advanced urothelial cancer.

Further Research Required to Find Biomarkers for Urothelial Cancer

Neeraj Agarwal, MD, director of the Genitourinary Oncology Program, Oncology Division, and professor of medicine at the Huntsman Cancer Institute, University of Utah, discusses the efficacy of nivolumab (Opdivo) and cabozantinib (Cabmetyx) versus sunitinib (Sutent) in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC) in the phase 3 CheckMate-9ER trial (NCT03141177).

Agarwal thinks the amount of progression-free survival (PFS) benefit has not been observed before in this setting. The PFS for nivolumab and cabozantinib doubled compared with sunitinib, with a hazard ratio of 0.51. The median PFS was 16.6 months with the combination versus 8.3 months with monotherapy for these patients.

It’s important to note that this trial population was representative of what has been seen in the real world, according to Agarwal. There were 20% of patients in the favorable-risk category, and these patient’s usual tend to do better overall. Sixty percent of patients were in the intermediate-risk category, and 20% of patients were in the poor-risk category. This makes the group of patients on the study similar to the number of patients in each risk category off clinical trials.

The overall survival led to a 40% reduction in risk of death for those receiving the combination with a hazard ratio of 0.60. The median survival has not been reached in either arm, but the hazard ratio shows significant improvement, says Agarwal.

<< View more regarding renal cell carcinoma

Neeraj Agarwal, MD, discusses the efficacy of nivolumab and cabozantinib versus sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma in the phase 3 CheckMate-9ER trial.

CheckMate-9ER Proves to be Efficacious in Advanced or Metastatic RCC

 As far as advice for the average clinician who has prostate cancer as part of their practice, No. 1 is you’re not alone. Reach out to colleagues or friends. That may be someone within your practice who you may have trained with, or it may be someone at your local academic center, or across the world. Now that we’re so connected, whether that’s phone, email, or other, it’s important. Generally speaking, sometimes these curbside consultations are difficult on either end. I’m sure it’s happened to all of us. But sometimes it’s a simple question, and sometimes we’re able to do formal evaluations of individual patients. That’s one important fact to learn.

Another is that we have a number of different drugs. Some of them are similar. But we don’t have a lot of head-to-head comparative data. For instance, an AR [androgen receptor] signaling inhibitor or a PARP inhibitor will have different labels, but some of them are overlapping. Learn to use at least one of them well. The PARP inhibitors may be used in other cancers, so maybe there’s expertise already. As long as the data are reasonable, using that one as preferred to others is absolutely fine because it’s probably better to use a drug correctly with some data than use another one incorrectly that may have a higher level of data. That’s important, and a factor.

Also, keep up. I’m not saying keep up on the overall data, but at least looking at buckets; these may come from guidelines, review articles, or CME [continuing medical education]-type discussions. I’ll give you 1 specific example. Since the December 2013 press release, and 2014 ASCO [American Society of Clinical Oncology annual meeting] and beyond, we know that we can make a major improvement in overall survival by adding one of these drugs. I don’t believe chemotherapy is crummy, but as a naysayer, chemotherapy, docetaxel, doesn’t do so much for metastatic CRPC [castration-resistant prostate cancer]. That same drug with a few cycles has a major benefit for metastatic castration-sensitive, or noncastrate disease. There are now a lot of drugs that do that.

I’m not even going to mention doublets vs triplets, in part because through at least 2019, we know from data sets that a lot of patients are still getting old-fashioned therapy such as ADT [androgen deprivation therapy] alone or ADT plus a nonsteroidal or old-fashioned antiandrogen. This shouldn’t never happen, but it should happen in a very small minority. We want to make sure at least in principle that patients are getting the right therapy. There’s no way any specific doctor, including myself, can know all of the data. But as a patient is sitting in front of you, at least look up guidelines, phone a friend, or say something like, “This is your situation, and these are the general options that I see. I’m going to look into them a little more and then we’ll call you,” if it can’t be done in real time.

Scott T. Tagawa, MD, FACP, shares clinical pearls and advice for the management of mCRPC.

Clinical Pearls for the Management of mCRPC

 Fortunately, we’ve already had a number of different agents approved over the last 10 years and going back further, and those are in prime time, already in use. Those same drugs have been or are being studied in earlier lines of therapy where we’ve seen—particularly moving from castration-resistant prostate cancer to noncastrate, or hormone-sensitive castration-sensitive disease—where their hazard ratio for overall survival is even bigger. We’re moving earlier.

Then we have combinations. We had rationale for instance to combine a PARP inhibitor and AR [androgen receptor] pathway inhibitor. We had a randomized phase 2 trial that was positive, and we just had a press release showing that combination is positive, importantly, for PARP inhibitors in an unselected patient population in terms of genomics. We don’t know the data, so I’m not ready to use that today, but that’s an example of something that has some scientific rationale, and then is being tested with initial safety studies followed by randomized phase 2, followed by randomized phase 3. That may become a standard of care. That’s one set of trials that we have excitement over in terms of maximizing our use of the current drugs.

There are a number of other drugs out there. We know that the AR pathway is the dominant pathway throughout the lifecycle of most patients and tumors, and we know that there are resistance pathways. Subverting resistance with bypass pathways, such as AKT, we know that actually works, thanks to a positive trial. However, that trial with an AKT inhibitor has some issues with tolerability, but in principle, we’re finding ways to get around some bypass pathways or to prevent lineage plasticity. For instance, with an EZH2 inhibitor, or some other epigenetic modifier to prevent lineage plasticity and transformation to neuroendrocrine small cell prostate cancer. There are other—I don’t necessarily want to say better or more potent, just because that may be true in cells—different types of AR pathway inhibitors, such as those targeting internal domain or AR degraders. Those have made their way from preclinical studies into the clinical realm.

We all want to get immunotherapy to work better. We have, at least in the United States, sipuleucel-T, which at least in older studies led to a significant overall survival advantage. There’s a subset for on-label use of immune checkpoint inhibitors. That subset is small, about 1 in 20 to 25. Importantly, it’s 0 out of 25 if you never check, so it’s important to check. But how can we come up with different immunotherapeutics or make the existing ones work better? I mentioned radiation, for instance, more specifically PSMA [prostate-specific membrane antigen]-targeted radiation in combination. But there are a number of phase 3 trials that we expect to read out in the next few years that may lead to combinations that improve or expand the population who may benefit from an immune checkpoint inhibitor, at least as defined by anti–PD-1 or PD-L1.

PSMA is probably the leading, but not the only, cell surface target for immunotherapy right now, including for CAR [chimeric antigen receptor] T cells, which are very important and may lead to some major improvements, but it’s slow. We’re proceeding cautiously in terms of safety with those.

What’s happening more quickly are the bispecific antibodies—most common would be a cell surface target such as PSMA with CD3, but there are other things that might be on the other end of the molecule. We know that paradigm works against CD19, for instance. In preliminary presentations, it can be safe, at least in the right hands, and there can be responses. These are moving fairly rapidly from phase 1 to phase 3, at least with one agent. That’s interesting. Staying on the theme of cell surface targeting, there are antibody-drug conjugates. So using some of the same types of cell surface targets such as, and I don’t mean to sound like a broken record, PSMA. There are other important cell surface targets such as CYP1. DLL3 is a very interesting cell surface target. They’re maybe in general adenocarcinoma castration-resistant disease at a low level, but more commonly to a higher level in small cell neuroendrocrine. There may be other targets such as B7H3 and others that are with drugs in development.

An expert in prostate cancer comments on emerging agents and combinations in the pipeline for the treatment of mCRPC.

Future Treatment Landscape of mCRPC

 There are a number of different questions that remain for PSMA [prostate-specific membrane antigen]-targeted radionuclide therapy in general, but I’ll narrow it to lutetium-PSMA-617, which probably applies to the other lutetium-PSMA–targeted small molecules. One is patient selection. I may argue that in someone who’s received every known therapy, who doesn’t have a clinical trial available or other therapies available, and has good performance status, that maybe I don’t need a PSMA-PET [positron emission tomography] to treat them, in part because 95% of patients in the VISION study had a positive PET, at least defined by at least 1 lesion lit up brighter than liver. Even with discrepancies that are another small group, an overall patient population would probably still benefit. That’s one question in my mind.

There are a lot of other questions that are in the setting of choices. There are now 4 phase 3 trials that I know of looking at lutetium-PSMA–targeted beta in early lines of therapy: 3 in chemotherapy-naive metastatic CRPC [castration-resistant prostate cancer], and 1 in conjunction with AR [androgen receptor] pathway inhibitors and ADT [androgen deprivation therapy] for noncastrates, ie, castration-sensitive hormone-sensitive metastatic disease. So earlier lines of therapy make sense. There‘s less likely to be PSMA-negative disease. As I mentioned in one of the first segments of this, those who are more heavily pretreated with AR-targeted therapy are more likely to lose AR pathway and PSMA. It’s less likely in those earlier disease settings. Radiation resistance pathways or alterations such as 

 are less likely in earlier lines of therapy. They’re more likely to benefit from an agent such as lutetium-PSMA-617. Does this work in earlier lines of therapy? We don’t know, but we’ll test those.

The other major part is combinations; we certainly are already testing these with-AR targeted therapy. In the VISION trial, a big proportion of the patients received AR-targeted therapy as standard of care and had lutetium-PSMA-617 added to that. But other types of therapy warrant additional study. We have some safety data and early efficacy data in combination with immune checkpoint inhibitors and PARP inhibitors. There’s at least 1 trial with concurrent lutetium-PSMA antibody and concurrent docetaxel. Those all make sense to me, besides assessing different lines of therapy. And then going back to one of the things I started with, in terms of patient selection, it’s not just imaging. Imaging is one thing. There’s the theragnostic paradigm: see what you treat. It makes sense; is the target there? But there are factors that are beyond that, including patient factors as well as likely tumor factors, such as genomics, that may play a role.

Scott T. Tagawa, MD, FACP, shares his thoughts on remaining questions for imaging and PSMA-targeted therapy for mCRPC.