RADIOLIGAND THERAPY IS FOR REAL — and as the technique is further developed it will assume an important role in the treatment of advanced prostate cancer. This article has benefited from review and comments by Dr. Scott Tarawa, Associate Professor Clinical Medicine, Weill Cornell Medicine

THE OPENING SALVO:

“Prostate-specific membrane (PSMA) is a receptor on the surface of prostate cancer cells that is revolutionizing the way we image and treat men with prostate cancer. … [T]argeted therapy for prostate cancer has, to date, predominately used Lutetium 177 (Lu) labeled PSMA peptides. Early clinical studies evaluating the safety and efficacy of Lu PSMA therapy have demonstrated promising results with a significant proportion of men with metastatic cancer, who had already failed other therapies, responding clinically to Lu PSMA.”

This quote above is from the March 2017 article in J Med Radiat Sci by Dr. Louise Emmett and colleagues from the University of New South Wales, Sidney, NSW, Australia. It is a most informative review of the current literature and a discussion of practical aspects of therapy.

RADIOLIGAND THERAPY (RLT) – WHAT IS IT?

Radioligand therapy (also called theranostics and endo-radiotherapy) refers to the linkage of a therapeutic radioisotope, either with a small molecule or an antibody, to the prostate-specific membrane antigen (PSMA) on prostate cells. This is an emerging “targeted” therapy with further refinements certain to be developed in the near future.

Prostate cancer has an excellent target in PSMA since 90% – 95% of prostate cancer cells express this marker — increasingly displayed in higher grade cancers. Although the PSMA antigen is predominantly expressed on prostate cells, there is low-level expression in the parotid and salivary glands, kidneys, and small intestines and these organs receive small doses of Lu-177.

RLT is not a new concept. Radioimmuotherapy using a monoclonal antibody linked to a radioactive particle was approved for treatment of lymphoma 15 years ago. It is anticipated that Lu-177 targeting the somatostatin receptor on neuroendocrine cancer will soon be approved.

At this point, regarding prostate cancer, the most researched isotope for treatment is the beta emitter Lutetium -177 (Lu-177), although there are parallel studies with the alpha emitter Actinium 225 — and others are on the way. The treatment has been ongoing in Europe for several years, notably in Heidelberg and Munich. Favorable patients may receive 3 – 4 cycles administered every 6 – 8 weeks.

Currently, although formal research is just beginning, there is abundant information establishing the safety and initial efficacy of radioligand therapy (RLT), as many hundreds of patients have been treated outside of clinical trials. RLT now is reserved for men with metastatic prostate cancer no longer responding to available therapies. It is likely that further research will place RLT earlier in the treatment sequence.

There is a rationale for the application of Lu-177 therapy at an early disease stage, since the penetration of the isotope is best aimed at tumors less than 1-3 mm in size, the maximal tissue penetration of this beta emitter. The relatively long half-life of Lu-177 is 6.73 days, supporting a useful therapeutic persistence in tumors.

This Commentary article will focus on safety and early efficacy of Lu-177 PSMA directed therapy. PCa Commentary Vol.110: Lutetium 177, a promising radioisotope for the treatment of prostate cancer [control+click link to follow] discussed Lutetium in detail covering the biological basis and pharmacology of treatment and some early trial data.

WHAT HAS BEEN REPORTED REGARDING THE SAFETY AND EARLY EFFICACY OF LU-177 RADIOLIGAND THERAPY? 

At this time it is appropriate to only touch lightly on safety and short-term efficacy data, since the reported studies are small and the patients were not stratified for risk, except that they were all patients with mCRPC failing prior therapies. The message is clear, however: in general 50% of the patients showed a > 50% decline in PSA and roughly 65% showed some response.

Briefly, regarding early EFFICACY:

  • At the European Society of Medical Oncology, 2017, an abstract by Hofman, Sanhu et al. reported the only prospective Phase II study of Lu-177 in mCRPC. Thirty patients received up to four cycles: “At interim analysis 17 patients (57%) achieved a PSA decline of >50%, including 11 (37%) with a decline of >80%.”
  • In another study of 40 patients the PSA dropped after the first cycle in 67%. Improvement in the follow-up Ga 68 PSMA PET/CT was concordant with the PSA decline. The PSA responses were unaffected by the response to prior chemotherapy. (Ferdinandius et al, J Nucl Med, 2017)
  • A multicenter German study of 145 men (of which 99 had PSA checked after treatment) is the largest trial reported to date. The patients received from 1 to 4 cycles and 60% exhibited any PSA decline. Over the full study of 1 – 4 cycles a PSA decline of >50% was seen in 45% of the men, usually occurring after the first cycle. Prior chemotherapy had no effect on the likelihood of response to Lu-177. (Rahbar et al. J Nucl Med, 2017)
  • A Heidelberg study of 30 patients reported that 42% showed a >50 PSA drop and the response was continuing through three cycles. (Kratochwil et al., J Nucl Med, Aug 2016)

For perspective, in the initial trial of docetaxel (Taxotere) that gained the drug FDA approval in 2004, of the group of men with advanced CRPC 48% showed a PSA decline of >50% with docetaxel as it is currently administered (Tannock et al. NEJM Oct 2004). The men in the docetaxel trial were considerably less heavily treated than in the Lu-177 studies. In the Emmett article (ibid) the overall range of PSA responses of >50% was estimated to between 30% and 70%, “which compares well to the PSA response rates achieved by chemotherapy agents in mCRPC.”

Briefly, regarding SAFETY:

  • In the Hoffman study (ibid) dry mouth occurred in 63%, nausea in 50%, and significant blood cell toxicity was seen in 17%. Following the first cycle, significant relief of bone pain and overall global health improved in 43% and 37%, respectively.
  • In the Rahbar study (ibid) significant ( i.e. Grade 3 or 4 ) anemia and reductions in white blood cells and platelets occurred in 10%, 3%, and 3%, respectively, in this heavily treated group of patients. Dry mouth was an important adverse event.
WHAT IMPROVEMENTS ARE NEEDED TO ADVANCE RADIOLIGAND THERAPY? 

The initial efficacy as noted above is a commendable beginning. However, as Emmett pointed out, up to one third of men treated will not respond. One concern is that tumor cells may not uniformly express high levels of PSMA. Also, “Heterogeneity of PSMA receptor activity within the tumor population may mean that some sites will not respond.” (Emmett, ibid) Major efforts are in progress to improve efficacy and safety of RLT.

The Prostate Cancer Foundation awarded three $1,000,000 grants for 2017 for studies to improve RLT. Grants were awarded to:

  1. Dr.Scott Tarawa and co-workers at Cornell Weill Medicine to perform a series of 3 prospective clinical trials and to assess biomarkers to identify patients most likely to benefit from treatment. Dr. Tagawa has been a pioneer in the US for development and research in RLT. His clinical trials intend to optimize the dose and schedule of PSMA-targeted radionuclide therapy and include:
  • A dose-escalation study testing higher and higher dose fractionation (split dose) of Lu-177-PSMA-617 (enrollment began January 2017).
  • A study combining Lu-177-PSMA linked with the small molecule 617 combined with Lu-177 linked to the antibody J591. This study tests the theory that by delivering a slightly lower dose of 2 different PSMA targeting drugs that a much higher dose can be delivered to tumors with fewer side effects (anticipated enrollment in early 2018).
  • A dose-escalation study of 225actinium-J591 antibody to deliver a powerful alpha emitter to tumors, avoiding organs such a salivary glands and kidneys (enrollment began October 2017).

For enrollment and discussion of eligibility regarding Dr. Tagawa’s studies the contact person is Lauren Emmerich: email [email protected]; and phone 212-746-1480.

2. Dr. Shahneen Sandhu and colleagues, Melbourne, to study the synergy of the combination of Dr. Shahneen Sandhu and colleagues, Melbourne, Lu-177 with the PARP-inhibitor olaparib, which prevents repair of DNA in cells  damaged by radiation. The theory being tested is that the combination will more effectively kill cancer cells.

3. Dr. Johannes Chernin and co-investigators, UCLA, for elucidating the mechanisms of effectiveness and resistance to targeted Lu-177 RLT.

CURRENTLY OPEN PROTOCOLS FOR ACCESSING TREATMENT WITH LU-177: 

In the US, treatment with PSMA directed RLT with Lu-177 is restricted to protocol participation. However, in Australia at several sites the therapy is available in accordance to local regulations. (See below)

Protocols open at Dr. Tagawa’s clinic:

  1. Protocol NCT03042468: “Phase I Dose-escalation Study of Fractionated 177Lu-PSMA-617 for Progressive Metastatic CRPC.” Eligibility requires progressive mCRPC disease despite hormone and chemotherapy. The study involves 8 visits over 12 weeks.
  2. Protocol NCT 00859781: “177Lu Radiolabled Monoclonal Antibody HuJ591 (177Lu-J591) and Ketoconazole in Patients with Prostate Cancer.” This is a randomized Phase II study of men with a rising PSA despite hormone therapy, but DO NOT HAVE METASTATIC cancer on scans. This protocol is available at multiple sites across the US. The rationale for this protocol is based on the penetration range of 1- 3 mm for Lu-177 which suggests the therapy is best applied at an early stage of cancer.
  3. Protocol NCT 03276572: “Phase I trial of 225Ac-J591 in patients with mCRPC.” This is a dose-escalation study of the alpha emitter 225Ac linked with the anti-PSMA monoclonal antibody J591.

Open Protocol at UCLA and Houston:
“Lutetium-177 (Lu177) Prostate-Specific Antigen (PSMA)-Directed EndoRadiotherapy.” This is a phase II trial assessing the clinical safety and efficacy of the treatment with a follow-up time frame of 48 months. Randomization is between two dose levels of Lu-177. Efficacy will be evaluated by the number of patients with a > 50% decline in PSA at 12 weeks from baseline. Eligibility: metastatic CRPC, PSMA PET/CT positive, with or without prior chemotherapy. Contact: Susan Cork: phone 713-341-3203; email [email protected], or Iza Tworowska, phone 713-358-6562; email [email protected]

Protocol to be opened at UCSF late 2017 or early 2018: Lutetium-177 PSMA directed RLT for
patients with metastatic CRPC having been treated with either Zytiga or Xtandi or both.

Lutetium-177 therapy is available in Australia with information on the website thereanostics.com.au. Opening soon are protocols of 177 Lu-PSMA vs cabazataxel and another for Lu-177 plus the PARP inhibitor. Contact phone +61 8 9091 1081; email [email protected]

BOTTOM LINE:

The treatment of prostate cancer by targeting the PSMA with radioisotopes, notably Lutetium-177, is now emerging as a safe and effective treatment for men with advanced prostate cancer who have progressed through current regimens. As further research improves the therapy it is likely that RLT will find a role earlier in the treatment sequence.

 

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