Category: Treatment Information

Zytiga Rejected in England as First Line Treatment for Advanced Prostate Cancer

The following is bad news for men in England with advanced prostate cancer. The rationale behind making this drug unavailable to men was cost. If anyone here in the US recommends we switch to the British system of health care, this should serve as a wakeup call against it. The therapy as described in the link below has been approved in the USA on the basis of two major clinical trials.

Janssen’s medication Zytiga (abiraterone) was recently rejected as a first-line treatment for newly diagnosed advanced prostate cancer on the National Health Service (NHS) in England following an initial draft recommendation from the National Institute for Health and Care Excellence (NICE). The negative recommendation means Zytiga won’t be made routinely available for men with newly diagnosed metastatic prostate cancer. As it is recommended now, Zytiga will only be prescribed through the NHS for these men once standard hormone treatment or chemotherapy has failed.

In two recent Phase 3 trials – STAMPEDE and LATITUDE – first-line therapy with Zytiga along with steroids and hormone therapy was found to  reduce the chance of cancer recurrence and improve survival, compared to hormone therapy alone. Patients were all at high risk of their disease spreading, and treated earlier, before their disease become resistant to standard hormone therapy. After three years, 83 percent of patients taking Zytiga, prednisolone, and hormone therapy remained alive, compared to 76 percent in the control arm. Also, the combination reduced the risk of disease worsening or death by 71 percent.

LATITUDE  included men with prostate cancer whose cancer had already spread at the time of diagnosis but who had yet to receive hormone treatment. The LATITUDE trial compared patients treated with standard hormone therapy to those treated with hormone therapy plus Zytiga and the steroid prednisone. The combination reduced the risk of death by 38 percent.

“Two clinical trials published last year provided compelling evidence of the huge potential benefit of abiraterone [Zytiga] for these patients,” Sir Harpal Kumar, chief executive of Cancer Research UK, said in a press release, expressing his disappointment.

NICE highlights its key reasons for not recommending the therapy because it couldn’t accurately estimate the drug’s cost-effectiveness based on the data submitted.  NICE concluded they could only recommend drugs that are clinically effective and show value for money compared to current treatment options. In this case, abiraterone has fallen short.  Janssen can now submit additional data to help NICE resolve these questions and review the revised data later this summer, before a final decision is made.

Following this draft recommendation, the Institute of Cancer Research (ICR) also expressed disappointment that Zytiga will not be made available to these patients as a first-line treatment, at least for now. The ICR is now calling for urgent discussions about the data supporting the drug’s effectiveness earlier in treatment as well as the drug’s price.

A No-Nonsense Look at Prostate Cancer Surgery

I recently came across an excellent review on the pros and cons of prostate cancer surgery as published by the Prostate Cancer Research Institute (PCRI). I am linking the review. If you are contemplating surgery, please read it and discuss it with your surgeon. You might also want to verify the opinions expressed in this article with him or perhaps consider other therapeutic options if they apply. This post and its contents is for informational purposes only. Even though I was a satified surgery patient in 1995, and speak highly of my Johns Hopkins surgeon, I realize each man’s situation is different so read and apply it accordingly.

PARP Inhibitors and Prostate Cancer- Keeping Cancer Cells From Repairing Themselves

Drugs targeting poly (ADP-ribose) polymerase (PARP) are helping patients battle back more effectively against cancer. An enzyme, PARP helps repair damaged DNA in cells, and while that’s a good thing in healthy people, it can be bad news for cancer patients. To prevent PARP from repairing DNA breaks in cancer cells, AstraZeneca developed Lynparza, a PARP inhibitor (PARPi) that secured approval in 2014 for use in advanced ovarian cancer treatment. The five-year survival rate in ovarian cancer is 92% when it’s caught early. However, it’s only 17% for stage IV ovarian cancer patients.

Lynparza’s advanced ovarian cancer approval was supported by trials showing that 34% of patients responded to it for an average of 7.9 months. At first, it was only approved for patients who’d seen their disease return following three or more prior treatments, but its approval was expanded in August 2017 to include its use as a maintenance therapy. When used as a maintenance therapy, Lynparza reduced disease progression or death by 70% in one trial and by 65% in a second trial. It also improved median progression-free survival and median overall survival.

Lynparza isn’t the only PARPi  that’s effective in ovarian cancer, either. Tesaro’s Zejula and Clovis Oncology’s Rubraca have also won FDA approval for use following trials that demonstrated their ability to prevent PARP from repairing DNA-damaged cancer cells.

Although ovarian cancer has been the focus of PARPi’s so far, the FDA-approved Lynparza for use in some breast cancer patients in January. Specifically, Lynparza can help metastatic breast cancer patients with mutations to BRCA, another cell repair gene. Because breast cancer is the most common cancer in the U.S., with 252,710 people newly diagnosed annually, and about 5% to 10% of breast cancer patients have a BRCA mutation, far more people are likely to benefit from PARPi soon. PARPis are also being evaluated for pancreatic cancer, triple-negative breast cancer, and metastatic prostate cancer. If those trials succeed, then PARPi could become some of the most commonly used cancer drugs.

TAK-700 (Ortoronel) and Phase 3 clinical trials

The drug, TAK-700 (Ortoronel) and Phase 3 clinical trials have been described in a blog published on this website on June 3rd, 2011. TAK-700 is an oral, non-steroidal, androgen (e.g. testosterone) synthesis inhibitor. It is being developed by the Takeda Oncology Company affiliated with Millennium. They are sponsoring safety and efficacy clinical trials in men with metastatic prostate cancer who have not had previous chemotherapy or who have had chemotherapy more than two years earlier for early-stage prostate cancer (elm pc004) or metastatic cancer who have received chemotherapy (elm pc005). The trials are evaluating the safety and efficacy of TAK-700 when combined with prednisone as compared with prednisone alone. End points of the study are delay in disease progression and increased survival times.

Zytiga (Abiraterone) Plus Prednisone Approved for Treatment of Earlier Form of Metastatic Prostate Cancer

On February 8th, the Janssen Pharmaceutical Companies of Johnson & Johnson announced that the U.S. Food and Drug Administration (FDA) has approved a new indication for Zytiga® (abiraterone acetate) in combination with prednisone for the treatment of patients with metastatic high-risk hormone-sensitive prostate cancer (HSPC). The approval is based on Phase 3 data from the pivotal LATITUDE clinical trial, which found that in patients with metastatic high-risk HSPC, Zytiga® in combination with prednisone reduced the risk of death by 38% compared to placebos.

This approval marks an important step in addressing the unmet needs of patients with metastatic high-risk hormone-sensitive prostate cancer by providing an option that has demonstrated improvement in overall survival.  Zytiga® (abiraterone acetate) plus prednisone could become a standard of care for these patients.

LATITUDE was a multinational, multicenter, randomized, double-blind, placebo-controlled clinical trial that examined the use of Zytiga® 1,000 mg once daily in combination with prednisone 5 mg once daily, compared to placebos in patients with newly diagnosed, metastatic high-risk HSPC, who had not received prior cytotoxic chemotherapy. All the patients received a gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy. The study data were presented at the plenary session of the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, and simultaneously published in The New England Journal of Medicine. The study showed Zytiga® in combination with prednisone reduced the risk of death by 38% compared to placebos. Additional data demonstrated statistically significant delay in time to initiation of chemotherapy for patients in the Zytiga® arm compared to those in the placebo arm.

The Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled LATITUDE study enrolled 1,199 patients with newly diagnosed metastatic, high-risk hormone-sensitive prostate cancer (HSPC), who had not received prior cytotoxic chemotherapy. The study was conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada. A total number of 597 patients were randomized to receive Zytiga® plus prednisone, while 602 patients were randomized to receive placebo. All patients received a gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy. High-risk disease was defined as having at least two of three risk factors at baseline: a total Gleason score of ≥8, presence of ≥3 lesions on bone scan, and evidence of measurable visceral metastases. Patients with significant cardiac, adrenal, or hepatic dysfunction were excluded. The median duration of treatment with Zytiga® and prednisone was 24 months.

Zytiga® (abiraterone acetate) in combination with prednisone is now indicated for the treatment of patients with metastatic hormone-resistant prostate cancer (HRPC) and with metastatic high-risk hormone-sensitive prostate cancer (HSPC). For additional details, see the following link.

Apalutamide (ARN-509) Approved to Treat Non-Metastatic, Hormone-Resistant Prostate Cancer

On Feb. 14th, the U.S. Food and Drug Administration approved apalutamide (Erleada®, previously  called ARN-509) for the treatment of non-metastatic, castration (hormone)-resistant prostate cancer (CRPC). Apalutamide could be administered in a clinical setting wherein men who are being treated with androgen (hormone) deprivation therapy (ADT) see their PSA levels begin to rise, but no metastases are visible yet on bone or CT scans. There were previously no FDA-approved treatments for non-metastatic CRPC, and patients typically continued to receive ADT, despite its diminishing benefit.

This FDA approval was based on results from a randomized phase 3 SPARTAN clinical trial presented at the February 2018 ASCO Genitourinary Cancers Symposium. The SPARTAN trial tested apalutamide versus placebo and whatever treatment the men were already given (mostly ADT), in 1,207 non-metastatic CRPC patients with rapidly rising PSA levels of doubling time 10 months or less. Patients selected for the trial had no distant metastases based on bone and computed tomography (CT) scans of the pelvis, abdomen, chest and head. Some patients had malignant local or regional (pelvic) lymph nodes no larger than  2 cm on the short axis.

Apalutamide was found to delay the time to metastatic disease by over 24 months on average (40.5 months in the apalutamide group vs. 16.2 months in the placebo group). This represents a 72% reduction in risk of metastasis or death. The full results have been published in the New England Journal of Medicine.

This website recently contained a blog on ARN-509 and the SPARTAN trial posted on November 10th, 2017. The similarities between apalutamide (ARN-509) and enzalutamide were noted.  Their chemical structures are indeed very similar. They differ only in two areas of the molecule where chemists who develop drugs would anticipate making changes. Enzalutamide contains a 5-membered heterocyclic ring with a carbon-sulfur double bond whereas apalutamide contains a carbon-oxygen double bond (carbonyl) in its place. In addition, enzalutamide contains a dimethyl group on heterocyclic ring whereas this is replaced by a fused cyclobutyl ring in apalutamide. Further comparisons and similarities will be noted in future posts.

 

A Phase 3 Trial Shows that Xtandi Reduces the Risk of Metastasis in Hormone-Resistant Prostate Cancer

According to results just recently presented at the February 2018 Genitourinary Cancers Symposium in San Francisco, treatment with Xtandi® (enzalutamide) reduced the risk of metastasis or death in hormone-resistant prostate cancer (CRPC) patients whose cancer has not yet spread beyond the prostate, Pfizer and Japan-based Astellas Pharma recently announced.

The Phase 3 PROSPER clinical trial evaluated whether adding Xtandi® to the standard androgen (hormone) deprivation therapy (ADT) was better than ADT alone in patients whose cancer had progressed based on rising PSA levels.  The 1,401 men in the study had increasing PSA levels, but no symptoms nor prior evidence of metastases. The Xtandi® –  ADT combination extended the time a patient remained alive and metastasis-free by nearly two years, compared to ADT alone. Patients with non-metastatic, hormone-resistant cancer are those whose prostate cancer worsens despite reduction of the amount of testosterone to very low levels with anti-androgen therapies. In such patients with non-metastatic CRPC, there is a high unmet need to delay development of metastases and the progression to advanced prostate cancer. There are currently no approved systemic therapies for patients with non-metastatic CRPC in the U.S.

The multi-national, double-blind PROSPER study (NCT02003924) assessed the safety and effectiveness of a once-daily, oral, 160 mg dose of Xtandi®, an androgen receptor inhibitor approved for treatment of advanced prostate cancer, in 1,401 men with CRPC on standard treatment with androgen deprivation therapy (ADT). Adding Xtandi® to standard ADT reduced the risk of developing metastases or death by 71% compared with ADT alone. Specifically, the combo treatment extended the time until a patient developed metastasis or died – the study’s primary endpoint – from 14.7 months to 36.6 months.

Xtandi® plus ADT also led to a 93% decrease in the relative risk of PSA worsening, delayed median time to PSA progression by 33.3 months, and prolonged median time to first use of antineoplastic (anticancer) therapy by 21.9 months, compared to ADT alone. Subsequent follow-up will enable the analysis of changes in overall survival, another of the study’s secondary endpoints.

Side effects with Xtandi® were consistent with those reported in prior studies in patients with metastatic CRPC taking this medication. Grade 3 (severe) or higher adverse events were observed in 31% of men taking Xtandi® plus ADT, compared to 23% with ADT alone. The most frequent severe events were hypertension and fatigue. In addition, major adverse cardiovascular events occurred in 5% of patients receiving Xtandi® plus ADT – compared to 3% with ADT alone. The group taking the combination treatment also reported three seizures (none in those taking ADT alone). Treatment discontinuation primarily due to adverse events was low with both treatments.

The information above was published on February 12th in Prostate Cancer News Today to which I heartily recommend a subscription.

Positive Early-Stage Study Results of ProstaVax, Another Prostate Cancer Vaccine.

OncBioMune’s investigational cancer vaccine ProscaVax reduced tumor growth in 70% of prostate cancer patients included in a Phase 1a study. The immunotherapy candidate consists of a combination of the PSA protein (a hallmark of prostate cancer) with the cytokines — molecules produced by immune cells — interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The clinical trial (NCT02058680)  is evaluating the safety and efficacy of ProscaVax in patients with recurrent prostate cancer and increasing prostate specific antigen (PSA) levels, who either have not been treated by or are not responsive to hormonal therapy.

Twenty patients received six intradermal injections of ProscaVax at weeks 1, 2, 3,7, 11, and 15 of treatment. The latest data show that ProscaVax increased PSA Doubling Time (PSADT) in 14 of 20 patients, or 70%. PSADT is the time needed to double the blood level of PSA and a key tool in assessing biochemical and clinical progression. This result indicates reduced tumor growth at a minimum of 31 weeks after the start of ProscaVax treatment. Also at 31 weeks of treatment, 15 of 18 patients showed increased immunity to PSA. Four of the 20 patients who completed ProscaVax therapy exhibited disease progression at 31 weeks. Three of the four did not show increased PSADT. Of note, one patient withdrew from the trial after 19 weeks without disease progression.

The findings add to previously reported positive safety data. Results at 19 weeks of treatment showed that ProscaVax stopped disease progression in 80% of patients. Slowing the PSA elevation, thus increasing PSADT in patients with relapsed and advanced prostate cancer, has been increasingly shown to improve disease prognoses. The company plans to enroll a total of 48 participants in this Phase 1a/1b study and anticipates its completion by December, 2018.

Enzalutamide (Xtandi) Delays Metastasis in Hormone-Resistant Prostate Cancer

Adding Xtandi® (enzalutamide) to hormone therapy reduces the risk of cancer spreading in patients with non-metastatic, hormone-resistant prostate cancer (CRPC), new Phase 3 trial data shows. Additional results were announced by Pfizer and Astellas Pharma, the drug developers. “Many prostate cancer patients who initiate hormone therapy will experience disease progression illustrated by a rising PSA level, and currently, there are no FDA-approved treatment options for patients with non-metastatic CRPC until they develop confirmed radiographic metastatic disease,” according to Dr. Neal Shore, MD, director, Carolina Urologic Research Center.

Pfizer and Astellas initiated the multinational PROSPER trial to determine the effects of Xtandi® in men with non-metastatic CRPC. The trial enrolled approximately 1,400 patients with prostate cancer that had progressed, based on rising PSA levels, despite androgen deprivation (hormone) therapy (ADT) but with no symptoms or other evidence of metastasis. Participants were randomly assigned Xtandi® plus hormone therapy or a placebo plus hormone therapy. The study’s primary endpoint was metastasis-free survival, which is the amount of time passed until the cancer spread.

Results seen in the PROSPER study showed that Xtandi® plus ADT delayed clinically detectable metastases compared to ADT alone in patients with non-metastatic CRPC whose only sign of underlying disease was a rapidly rising prostate-specific antigen (PSA) level.  Xtandi® is already established as a standard of care for men with metastatic CRPC based on the results of prior studies, such as AFFIRM and PREVAIL, which demonstrated that Xtandi® delayed disease progression and improved overall survival in men with clinically detectable metastatic disease. For additional information, see the following link.

It seems that Xtandi® (enzalutamide) and ARN-509 (apalutamide) share similar biological properties and mechanisms of action. Perhaps there differences in pharmacologic properties due to their differing chemical structures but they seem similar. (See the Nov. 10th post for comparison.)