Interview with Dr. Bital Savir-Baruch on the TheraP study: 177Lu-PSMA-617 vs cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) Phase 3 trial

RADIOLABELED SMALL MOLECULES that bind to prostate-specific membrane antigen (PSMA) such as 177Lu-PSMA-617, which delivers β radiation to PSMA-expressing cells, are proving to be promising treatments for metastatic castration-resistant prostate cancer (mCRPC). Updated data from TheraP (ANZUP 1603), a Phase 2 trial of 177Lu-PSMA-617 versus cabazitaxel in patients with mCRPC, presented at the 2021 ASCO Genitourinary Cancers Symposium, showed a higher prostate-specific antigen (PSA) response and a superior safety profile with 177Lu-PSMA-617. TheraP is the first randomized controlled trial to compare a direct targeted radioligand with standard-of-care therapy. The latest results were also published concurrently in The Lancet.

Patients enrolled in TheraP had PSMA-positive mCRPC and no sites of metastases with discordant 2-[18F]fluorodeoxyglucose (FDG) positive and PSMA negative findings. All patients had progressive disease after treatment with docetaxel and some had received abiraterone or enzalutamide; cabazitaxel would have been considered the next appropriate treatment. At 12 months, progression-free survival (PFS) was 19% in the 177Lu-PSMA-617 group compared with 3% in the cabazitaxel group. Longer follow-up is needed to evaluate the effect of 177Lu-PSMA on overall survival. Fewer grade 3/4 adverse events were recorded with 177Lu-PSMA-617 (33% vs. 53% with cabazitaxel) and scores for several patient-reported outcomes also favored 177Lu-PSMA-617.

GU Oncology Now spoke with Bital Savir-Baruch, MD, to review the results and implications of TheraP. Dr. Savir-Baruch is Assistant Professor, Radiology and Medical Imaging at Loyola University Medical Center, Maywood, IL.

GU Oncology Now: What are your key takeaways from the study?

Dr. Savir-Baruch: The results of this study are important. Overall, we see fast growth in the development and clinical use of radioligand therapeutics in the practice of nuclear medicine (aka theranostics). Understanding the unique benefit of these therapies on a specific population is essential. Therefore, understanding the application of the therapeutic radiopharmaceutical 177Lu-PSMA-617 in different populations applies to the same concept. This study taught us that treatment with 177Lu-PSMA-617 could benefit patients with PSMA-positive mCRPC who had progressive disease after treatment with docetaxel.

Did any of the study’s findings come as a surprise to you?

Not really. The PSMA theranostics follows the concept of “lock and key.” As long as the PSMA expression is present in the tumors (which was part of the enrollment criteria), the drug should hypothetically work. Yet, it is essential to investigate the effect of this treatment in a different population, including patients with mCRPC, which is a very challenging population to treat. In this study, all patients had both PSMA PET scan and FDG- PET screening to confirm the PSMA expression at all disease sites, so I can’t say that it surprised me. It taught me that PSMA expression is high enough in the mCRPC population that it can result in a better outcome than the standard of care chemotherapy.

What patient population do you think would be most likely to benefit from 177Lu-PSMA-617 as an alternative to cabazitaxel?

I think the question that we would like to ask is what patient population will benefit from 177Lu-PSMA-617? This question can only be answered by additional prospective clinical studies. Based on this study, we now know that 177Lu-PSMA-617 affects the mCRPC population that is already resistant to docetaxel and with PSA ³20 ng/mL and rising. The VISION study, investigating the use of 177Lu-PSMA-617 in patients with PSMA-positive mCRPC, recently announced that the study met both primary endpoints of improving overall survival (OS) and PFS compared with best standard care.

Additional populations to investigate, for example, will be patients with newly diagnosed prostate cancer with widespread metastatic disease (metastatic hormone-naïve prostate cancer [mHNPC]) or patients with recurrent metastatic disease (metastatic hormone-sensitive prostate cancer [mHSPC]) who are candidates to initiate androgen deprivation therapy. TheraP clinical trial has already begun a phase 2 study (the UpFrontPSMA trial) comparing sequential 177Lu-PSMA-617 and docetaxel with docetaxel alone in patients with mHNPC. An additional question to answer regarding 177Lu-PSMA-617 is what to do if a patient responded to the approved number cycles of 177Lu-PSMA-617 and now recurs or progresses after a given time. Will the patient benefit from a subsequent course of therapy?

What insight has this study provided into 177Lu-PSMA as a promising new therapeutic class for men with mCRPC?

We have to continue to learn about what treatment is most effective in mCRPC. It will be interesting to identify combinations of treatments and their toxicities. As the taxane mechanism of action is entirely different from 177Lu-PSMA-617, it will be interesting, for example, to investigate how effective 177Lu-PSMA-617 is if given with, before, or after cabazitaxel.

In the meantime, I would predict that people would favor treatment with 177Lu-PSMA-617 knowing it had a better outcome and less toxicity. From my experience using 177Lu-DOTA-TATE for neuroendocrine tumors, I know that physicians feel much more comfortable with this class of treatment than any systemic chemotherapy. It’s probably going to be similar for prostate cancer, given what we’ve seen from the clinical trials.

In your practice as s a nuclear medicine physician, how will the results of the TheraP study impact your treatment options?

With the new approval of diagnostic and therapeutic radiopharmaceuticals, we predict significant growth in our nuclear medicine practice. In general, once a therapeutic agent is incorporated into our clinical practice, most patients are referred to us by their hematologist-oncologists. At this point, we become their consulting service until all the treatment cycles are completed. Our patient care includes a consultation with the patients and their families. At this meeting, we evaluate their eligibility for the treatment, prepare them for the treatment administration, review radiation safety and home instructions, and discuss expectations of treatment outcome. We have a full theranostic administration practice at our institution, including a radiation safety team, nurses, nuclear medicine technologists, and nuclear medicine physicians. I believe our practice will grow significantly with the approval of 177Lu-PSMA-617.

Do you have any additional comments on the impact of these latest findings?

177Lu-PSMA-617 appears very promising for patients with metastatic prostate cancer. The TheraP trial looked at a very advanced population (mCRPC), similar to the VISION trial. In addition, we would like to understand the effect of 177Lu-PSMA-617 in different patient populations, such as the non-castration-resistant prostate cancer population. Also, what is the best time to administer the therapy? What is the OS and PFS if administered earlier in the care of patients with oligometastatic disease when compared to patients with widespread disease? As I mentioned before, it will be very interesting to see if patients can benefit from additional cycles of 177Lu-PSMA-617 if or when they progress sometime after completion of the investigated six cycles.

References

Michael S Hofman, Louise Emmett, Shahneen Kaur Sandhu, et al; ANZUP Cancer Trials Group. 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant pros- tate cancer (mCRPC) progressing after docetaxel: Updated results including progression-free survival (PFS) and patient-reported outcomes (PROs) (TheraP ANZUP 1603). J Clin Oncol. 2021;39(6, suppl):3. Abstract 6. doi:

Hofman MS, Emmett L, Sandhu S, et al; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-la- bel, phase 2 trial. Lancet. 2021;397(10276):797-804. doi: 10.1016/S0140-6736(21)00237-3.

Dhiantravan N, Emmett L, Joshua AM, et al. UpFrontPSMA: a randomized phase 2 study of sequential 177Lu-PSMA-617 and docetaxel vs docetaxel in metastatic hormone-naïve prostate cancer (clinical trial protocol). BJU Int. Published online March 7, 2021. doi: 10.1111/bju.15384.

Novartis announces positive result of phase III study with radioligand therapy 177Lu-PSMA-617 in patients with advanced prostate cancer. Novartis, March 23, 2021. https://www.novartis. com/news/media-releases/novartis-announces-positive-result-phase-iii-study-radioli-gand-therapy-177lu-psma-617-patients-advanced-prostate-cancer

Morris MF, De Bono JS, Chi KN, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). 2021 ASCO Annual Meeting, Plenary Session, June 6, 2021. Abstract LBA4. https://meetinglibrary.asco.org/session/13668