PCa Commentary | Volume 153 – May 2021

Posted by Edward Weber | May 2021

PSMA Targeted RadioIigand Therapy for Metastatic Prostate Cancer: Where We Currently Stand and Where Research is Heading

Radioligand Therapy (RLT) targeted with the radionuclide Lutetium-177 or Actinium-225 has been found in early studies to be promising, safe and effective. A Gestalt of results has generally shown about a 50% PSA decline in 50% of patients and a median progression-free survival (mPFS) in the range of 7 – 9 months. Overall survival data is less meaningful due to the wide disparity of patient characteristics studied. 

The prostate specific membrane antigen (PSMA), expressed at the cell membrane of over 95% of prostate cancer cells, was identified in 1987 and is the target for RLT. The radionuclides binding with this target mainly have been the beta emitter Lutetium-177 (Lu177) or the alpha emitter Actinium-225, but several others are being researched.

The patients in studies have generally been men with heavily pretreated disease, although one study addressed men with earlier metastatic disease (only prior ADT and docetaxel) and found a mPFS of

27 months. With the forthcoming final report from the 750-man international VISION trial, the first phase of RLT investigation will be drawing to a close. Forthcoming are studies of combinations of RLT with chemotherapy, immune checkpoint inhibitors and Radium-223, and others. The future direction will be towards moving this therapy earlier in the course of the disease, when there is a lower tumor burden and fewer acquired adverse mutations. This Commentary will review the results of the studies to date and indicate protocols exploring new treatments. 

An excellent review of outcomes of reported and future trials was presented by Dr. Scott Tagawa, et al.,Weill Cornell Medicine. (Current Oncology Reports. 2021)

The first prospective Phase II trial of Lu177 was reported by Hoffman et al., (Lancet Oncol, 2018), regarding a study of 50 heavily pretreated men with metastatic castration-resistant prostate cancer (mCRPC). PSA decline of >50% was seen in 64% of patients, and 44% showed a decline of >80%. 

In the initial cohort of 30 men, “Biochemical progression-free and overall survival were 7.6 months and 13.5 months, respectively.” The most common side effects were nausea, fatigue, and dry mouth. Hematologic toxicity was minimal.

A prospective randomized trial (TheraP) reported a comparison of Lu177 to the chemotherapy drug cabazitaxel in 200 men with mCRPC pretreated with docetaxel chemotherapy.  A >50% PSA decline was seen in 66% of 200 men receiving Lu177 vs 37% for cabazitaxel. At median follow-up of 18.4 months, progression-free survival for Lu177 was 19% vs 3%. Adverse events were more frequent in the cabazitaxel group (JCO, Feb 2021).

A recent New Zealand report of Lu177-PSMA therapy in men with mCRPC found an 18-month overall survival estimate of 63.8%. “Patients with baseline serum PSA <20 ng/mL had a greater 18-month estimated survival (79%) compared to PSA > 20 ng/mL (53.8%)” (J Med Imaging Radiat Oncol 2021 Apr 22). This underscores the impact of early treatment.

Looking To the Future:

The message from the many reported studies is clear and not surprising: optimal patients for RLT are those with minimal pretreatment, lower PSA values, lower tumor burden, and good performance status — and this is the direction in which future trials and research are heading. It is likely in the near future that many men with mCRPC will have been treated with Lu177 earlier in the course of their disease.

The now-completed international VISION trial testing Lu177-RLT in heavily pretreated men with mCRPC found the combination safe and effective. Novartis, the sponsor, has reported that the final analysis of the data is complete and the outcome for RLT was very favorable. It will be reported at a forthcoming international meeting. The FDA will likely give its approval for general use in men with the same disease stage as those in the study.

Upcoming Multicenter Trials:

Dr. Scott Tagawa, Professor of Medicine and Urology, Weill Cornell Medicine (and senior author of the article cited earlier), has kindly provided to this Commentary a list of upcoming large multicenter trials (personal communication):

• “PSMAddition for non-castrate / hormone sensitive metastatic prostate cancer (ADT+AR pathway inhibitor [to be] randomized to early vs delayed Lu177-PSMA-617).
• PSMAfore for mCRPC after 1 line of AR pathway inhibitor (alternative AR pathway inhibitor [to be] randomized to early vs delayed Lu177-PSMA-617).
• SPLASH for mCRPC after 1 line of AR pathway inhibitor (alternative AR pathway inhibitor randomized to early vs delayed PNT 2002 aka Lu177-PSMA I&T).
• Lu177-PSMA-617 versus docetaxel for mCRPC following [a] pathway inhibitor (Canadian study).

A Sampling of Other Protocol Regimens:

Studies proposed for men with mCRPC —

• Lu177-PSMA-617 is being studied in randomized trials in combinations with Actinium-225; the checkpoint inhibitor, Ketruda; PARP inhibitors, Radium-223, enzalutamide, Yttrium-90 microspheres, and ketoconazole.
• Studies are evaluating the safety and efficacy of repeat courses of RLT in men who initially responded to treatment and then progressed.
• Studies of Lu177 combined with chemotherapy: 

1. 1. An Australian trial, UpFrontPSMA, will study two cycles of Lu177 followed by 6 cycles of docetaxel vs docetaxel alone in men with castration-sensitive metastatic disease.
   2. Lu177 was tested in men with mCRPC who had been treated with chemotherapy vs men naive to chemotherapy, who were generally earlier in their disease course. The radiographic-free and overall survival in the chemo-naive cohort were 8.8 and 27.1 months, respectively. (Barber et al., Journal Nuclear Medicine. 2019)

• ENZA-p protocol (ANZUP 1901 [Australia]) comparing ENZ (enzalutamide) vs ENZ + Lu177 in men with mCRPC, PSADT <2.8 mo and PSA progression after ADT and Zytiga.

Studies in earlier stages of prostate cancer —

• A trial randomizing  Lu177 in the salvage setting after prostatectomy.
• In Australia, where Lu177-RLT is more available than in the U.S., RLT has been used in connection with Stereotactic Ablative Radiotherapy treatment in patients with PSA-recurrent disease to address small tumors and suspected micrometastatic cancer.

BOTTOM LINE:

Since RLT’s introduction into clinical practice in 2015, it has become a very promising therapy with varied applications. Its unique biology allows nearly exclusive targeting of the PSMA antigen on prostate cancer cells, effecting lethal double-stranded DNA breaks in a manner similar to external beam and brachytherapy. As such, its biology offers an alternative or complementary option to the standard targeting of the androgen receptor in the treatment of prostate cancer.

“I want to thank Dawn Scott, Staffperson, Tumor Institute Radiation Oncology Group, & Mike Scully, Librarian, Swedish Medical Center for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible.”