First-Ever Clinical Trial Testing PSMA-Targeted Antibody and Radioactive Alpha Particles for Treatment of Advanced Prostate Cancer

Radiation is one of the most common treatments for prostate cancer. Using radiation, physicians are able to cure some men with cancer confined to the prostate, as well as improve symptoms for men with metastatic disease. There are many different types of radiation treatments.

One type of treatment includes injecting radioactive isotopes into the blood in order to directly reach the prostate cancer cells regardless of where they are located in the body, including the cells that have spread to the bone and other organs. For example, Radium-223 (Xofigo) is FDA-approved to treat prostate cancer that has metastasized to the bone and has been shown to improve both the quality and duration of the lives of men with advanced prostate cancer.

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Red marker = PSMA, Green = radiation, demonstrating that the drug targets the cancer cell directly.

Radioimmunotherapy or radioligand therapy involves the practice of attaching a radioactive isotope to a cancer-targeting antibody or small molecule that binds only to a specific cancer-related molecule on a tumor cell. This is similar to a “lock and key” scenario, where the antibody or molecule resembles the key that will only recognize a very specific lock (the cancer-related molecule).

Essentially all prostate cancers have a specific “lock” called prostate-specific membrane antigen (PSMA). This “lock” is a protein that sits on the surface of most prostate cancer cells but is absent from most other normal places in the body.

Physicians and scientists have engineered very specific “keys” in the form of monoclonal antibodies and molecules that will bind only to PSMA. When we attach radioactive particles to these keys, we are able to deliver what we call “molecularly targeted” radiotherapy.

For example, J591 is a monoclonal antibody (an engineered protein) that recognizes PSMA. Actinium-225 (225Ac) is a small radioactive particle that emits alpha-particles, a powerful form of radiation requiring fewer particles to cause damage to the cancer cells. When these are attached to one another, we call the compound 225Ac-J591 (a radioactive particle linked with a monoclonal antibody). It is designed so that J591 will recognize the PSMA on the prostate cancer cells and bring the radioactive particle 225Ac with it into prostate cancer cells wherever it goes in the body.

Our physicians and scientists are building on prior laboratory-based research presented at the 2017 Meeting for the Annual Association for Cancer Research (AACR) and are now studying the role this experimental therapy may have for men with advanced prostate cancer that has spread throughout the body. Thanks to generous support from the Prostate Cancer Foundation and the NIH SPORE award, Dr. Scott Tagawa, medical oncologist and Director of the Weill Cornell Medicine Genitourinary (GU) Oncology Program, and his team are conducting the first-ever clinical trial testing the PSMA-targeted antibody and radioactive alpha particles (225Ac-J591) for treatment of advanced prostate cancer. This promising new and unique approach has the potential to lead to another treatment option for those patients who are not experiencing the best clinical outcomes possible from standard of care therapies. Some men in Germany have received 225Ac linked to PSMA-617 with a handful of cases published with impressive responses. However, no formal studies have been performed and there are reports of bothersome dry mouth (xerostomia) and the potential for delayed kidney damage (seen in mice).

“We look forward to advancing science and also making this treatment available to men with advanced prostate cancer in the near future, says Dr. Scott Tagawa. “Our goal is to translate the existing knowledge base into true clinical gains for prostate cancer patients and it’s great that in October, 2017, we are able to treat our first patient.”

 

 

 

Success of Abiraterone Trials Prompts ‘Mind Shift’ in Prostate Cancer Treatment

The below has been adapted and excerpted from an article in Healio in which Dr. David Nanus HeadshotNanus comments on The LATITUDE and STAMPEDE trials — results of which were presented at this year’s ASCO Annual Meeting and subsequently published in The New England Journal of Medicine. Read the full story here.

Abiraterone acetate is poised to challenge docetaxel as the standard addition to androgen deprivation therapy for treatment of newly diagnosed, metastatic castration-resistant prostate cancer. The LATITUDE and STAMPEDE trials showed the addition of abiraterone acetate and prednisone to androgen deprivation therapy (ADT) reduced risk for death by nearly 40%.

Docetaxel — an IV chemotherapy — can cause nausea, constipation, diarrhea, neutropenia or fatigue during its 18-week dosing schedule. Abiraterone, an oral adrenal inhibitor traditionally used in later-line therapy, is administered until disease progression and has relatively few side effects.

Docetaxel became the standard of care in patients with metastatic hormone-resistant prostate cancer following results from the CHAARTED study, published in 2015 in The New England Journal of Medicine. The results, based on median follow-up of 28.9 months, showed docetaxel improved median overall survival (OS) from 44 months to 57.6 months.

Abiraterone typically has been reserved as second-line therapy for men resistant to ADT. The LATITUDE and STAMPEDE trials — both supported by Janssen, the manufacturer of abiraterone — evaluated whether abiraterone would be more beneficial if used earlier.

Although abiraterone conferred unprecedented survival benefits and is better tolerated, not all oncologists agree it should replace docetaxel in the absence of a head-to-head comparative trial.

HemOnc Today asked urologic oncologists and researchers about the promise of abiraterone; the potential impact of its long-term use; if its cost in comparison with docetaxel is prohibitive; and whether abiraterone soon will be challenged by other therapies for the treatment of metastatic hormone-resistant prostate cancer.

“Abiraterone is a whole new paradigm because your patient is not coming in for an infusion every few weeks for six cycles,” David M. Nanus, MD, professor of medicine and urology at Weill Cornell Medicine, told HemOnc Today. “With six cycles of docetaxel, patients are often wiped out by the time they’re done, and it might take a few months to recover afterward.”

Based on the findings of the LATITUDE and STAMPEDE trials and the potential of targeted therapy, oncologists with whom HemOnc Today spoke agreed researchers are on the precipice of significantly extending the lives of men with prostate cancer.

In addition to the enthusiasm surrounding abiraterone and its potential to be the new standard of care in the treatment of metastatic, castration-resistant prostate cancer, several ongoing clinical trials are investigating other strategies to reduce androgen exposure. Results of those trials also could be practice changing, and again raise questions about the standard of care.

 

2017 Genitourinary Cancers Symposium Day 3

gu_symposium_2017_img_3054The third day of the 2017 Genitourinary Cancers Symposium started with a Best of Journals session on renal cell carcinoma (the most common form of kidney cancer) and the early poster sessions focused on renal cell, testicular, penile, and urethral cancers.

The first major morning session was focused on “novel targets and controversies in advanced testicular cancer.” Experts in the field first discussed actionable targets in testicular tumors, also referred to as germ cell tumors. This session also addressed a debate regarding treatment intensification in the subset of patients with “poor prognosis” – or germ cell tumors whose blood tumor markers do not decline optimally after initial chemotherapy. This subject remains controversial, but fortunately only affects a small number of patients, as in the current treatment era, after initial chemotherapy treatment, approximately 95% of all patients diagnosed with testicular cancer will be cured.

linehanThe Keynote Lecture on renal cell carcinoma was delivered by Dr. Marston Linehan from the National Cancer Institute. He discussed the current state-of-the-art treatment which is based upon decades of research largely led by him on the genetic basis of renal cell carcinoma (RCC). Several of his discoveries about the genomics and biology of RCC have led to the current wealth of drugs available to treat this disease. One such discovery was the importance of the von Hippel Lindau gene in patients with familial cancer syndromes that also affects tumor genomics in most patients with clear cell RCC. This discovery led to investigation in targeting the VEGF pathway which is the backbone of most currently approved drugs.

The session on the diagnosis and treatment of local renal cancer (confined to the kidney) started with a presentation on the role of active surveillance or watchful observation in small renal tumors, and was followed by discussions on imaging and biopsy of renal masses. A talk about the use of ablation in small renal tumors was followed by an abstract presentation on a registry of active surveillance of patients with small renal masses.  In summary, experts in the field discussed strategies and data behind the options of imaging and/or biopsy followed by either close surveillance or minimally invasive treatment strategies for patients with small renal masses.

The oral abstract scientific presentation session featured a presentation that followed up on the morning theme of small renal masses, also discussing surveillance, imaging, and circulating biomarkers. The Mayo Clinic group highlighted the success of treating carefully selected healthy patients with cryoablation in an expert center. A novel computer-assisted technique appears to be useful in assessing response to therapy compared to standard radiology assessment. A collaborative group led by Drs. Pal and Choueiri presented results of a large group of patients who had assessment of circulating tumor DNA (cfDNA) with a commercial platform prior to first-line or subsequent lines of treatment for metastatic disease.  Additionally, an Italian group presented an abstract on changes in tumor burden and prognostic classification when patients with metastatic RCC utilize an active surveillance strategy rather than take medications or undergo a local procedure. This is important to realize that for carefully selected patients, just because there are metastatic (spread) tumors on scans, immediate treatment is not always necessary. Sometimes these remain stable over long periods of time without treatment and this can be discussed with experienced clinicians.

Kidneys_GU Blog_FBThe final session of the conference reviewed the opportunities and challenges in systemic therapy for advanced kidney (renal) cancer. Imaging techniques to optimally evaluate one’s response to targeted therapies was discussed, highlighting examples of successful treatment with very little change in tumor measurements by traditional techniques. For example, it’s possible for a tumor to appear the same size after treatment by standard measurement, but it can be 95% necrotic (dead) tissue and in this scenario, the patient feels better and may live longer. This would be classified as non-response (or stable disease). Unfortunately, for patients with larger or more invasive tumors, many patients are not cured with surgery alone despite normal scans elsewhere in the body. Dr. Karam reviewed the results of recently presented trials utilizing targeted therapy following surgery. While these are not quite ready for primetime, the medical community is currently awaiting the results of other studies well as current studies utilizing immune checkpoint inhibitors in combination with surgery. Drs. Vaishampayan and Jonasch discussed the multiple different treatment options available to physicians and patients with advanced RCC. Physicians were reminded to consider referral to a highly experienced center for high-dose interleukin (IL)-2, a treatment which offers long-term disease-free survival off therapy in a selected subset of patients with advanced kidney cancer. Current studies are ongoing to assess different drug combinations, as well as novel agents. The last presentation of the conference was led by Dr. Powles who presented a late-breaking abstract on the randomized phase II study of atezolizumab with or without bevacizumab versus sunitinib in patients with advanced previously untreated metastatic RCC. While not definitive, the results were intriguing and support the continuing phase III study assessing the use of the combination of atezolizumanb and bevacizumab. There are multiple new studies looking at combinations of drugs and we encourage patients interested in this type of treatment to look for sites that are enrolling.

Overall, the conference was a great opportunity for both academic and community physicians from all different specialties (including medical oncology, urology, radiation oncology, radiology, and pathology) to mix with and learn from each other.  We look forward to participating next February in San Francisco for the 2018 Genitourinary Cancers Symposium.