About 10% to 20% of all prostate cancers are classified as castrate-resistant prostate cancer (CRPC). CRPC occurs when prostate cancer evolves to resist standard treatment with androgen deprivation therapy (ADT), which blocks the production and signaling activity of hormones called androgens (such as testosterone) that fuel the cancer’s growth. Most CRPCs are diagnosed as metastatic (mCRPC), meaning they have already spread beyond the prostate; only about 16% are caught prior to metastasis (non-metastatic CRPC, or nmCRPC).
After CRPC develops, more potent drugs that further reduce androgen signaling may help for a while, but the cancer eventually resists these as well. No cure yet exists for mCRPC, but prolongation of survival is possible with new treatments, some of which have been approved by the U.S. Food and Drug Administration (FDA) or are being evaluated in clinical trials. Read on to learn more about new treatments for CRPC.
New Treatments for mCRPC
mCRPC remains a clinically challenging late-stage cancer with no curative treatment options. However, the newer hormonal drugs enzalutamide (brand name XTANDI) and abiraterone (ZYTIGA, which is given with prednisone) provide a tighter inhibition of androgen signaling, and are often used as first-line treatment in mCRPC. Docetaxel (chemotherapy) is used in patients for whom treatment with enzalutamide or abiraterone has failed, but it can also be a first-line treatment for mCRPC—this is a decision usually made by oncologists that takes into account patient-specific considerations. Bone metastases, very prevalent in prostate cancer, are treated with Radium-223 (Xofigo) or radiation to reduce pain.
In recent years, what has changed in treatment of mCRPC is that clinical guidelines now include mutational testing and analysis of markers to predict the potential effectiveness of newer treatments that involve the immune system.
Mutational and genetic testing in mCRPC
All cancers, including prostate cancer, arise because of genetic mutations in cells. The first type mutations to be appreciated as causative in driving mCRPC were in genes involved in repair of damaged DNA. These mutations, often hereditary, were identified long ago as predisposing to the development of breast and ovarian cancers in women.
In prostate cancer, mutations in one of these DNA-repair genes (BRCA2, BRCA1, CHECK2, ATM, and a few others) are found mostly in late-stage prostate cancer in about 12% to 20% of patients. These mutations predict whether treatment with drugs known as PARP inhibitors might be effective. The FDA has already approved two drugs in this category: olaparib (Lynparza) and rucaparib (Rubraca). New clinical guidelines now dictate testing for these mutations (molecular profiling) in tumors of mCRCP patients.
A recent study reported that men with deficiencies in one of 13 genes related to DNA damage repair had a higher response rate and a longer progression-free and overall survival when treated with the PARP inhibitor olaparib versus an anti-androgen treatment.
A new drug called berzosertib, an inhibitor of the DNA-repair protein ATR, has shown very promising results in a variety of cancers with relevant mutations, and is currently being tested in a trial for mCRPC in combination with chemotherapy.
If you’re wondering whether molecular testing for mutations could help guide treatment for your or your loved one’s metastatic castrate-resistant prostate cancer, register to receive a personalized, free Cancer Commons Treatment Options Report.
Immune checkpoint inhibitors (ICIs) in mCRPC
This class of drugs fall into the category of immunotherapy—drugs that boost the immune system to fight cancer. ICIs have significantly improved outcomes in a number of types of metastatic cancer, but were previously thought not to have much promise in mCRPC. This is still true, by and large, but a small proportion of mCRPCs may have a feature that is associated with a high probability of response to immunotherapy drugs. This feature is known as mismatch repair deficiency or microsatellite instability, and is quite rare in prostate cancer (seen in about 3% of cases). Patients whose tumors have this feature should be offered an ICI called pembrolizumab (Keytruda).
Another potential marker of sensitivity to ICIs is loss of the gene CDK12, a mutation seen in about 7% of mCRPC patients. A small study demonstrated that 33% of these patients experience reduction in PSA levels in response to ICIs.
There are now multiple clinical trials exploring ICIs in combination with other drugs—including targeted therapy, hormonal drugs, or drugs that block the blood supply to tumors, as well as PARP inhibitors.
Other new approaches in mCRPC
Other drugs in clinical trials for mCRPC do not rely on the presence of defined mutations. Here, I discuss only those that already have promising preliminary results:
Most prostate cancer cells express a protein called PSMA on their surface. In fact, PSMA is almost exclusively found on prostate cancer cells, making it a good therapeutic target. The novel drug 177Lu-PSMA-617 (LuPSMA) is a radioactive molecule attached to another molecule that specifically targets cells expressing PSMA. The most recent results from a randomized clinical trial where men received either LuPSMA or the chemotherapy drug cabazitaxel show that response rate (a decrease in PSA) was higher with LuPSMA than with cabazitaxel.
Currently, there are two other radionuclide conjugates that target PSMA in trials: BAY 2315497 and 225Ac−J591.
PSMA can also be targeted by other means, one of which is a very interesting approach known as CAR T-cell treatment, currently available in two trials. CAR T-cell treatment is beneficial in “liquid tumors” of the blood or bone marrow, but has yet to be validated in “solid tumors” like prostate cancer. However, some results are promising. The presence of a good target (PSMA) for these engineered cancer-killing immune cells is a good omen in prostate cancer, because identifying specific targets in solid tumors is a major hurdle in designing CAR T-cell treatments.
PSMA-based radioactive molecules are also used (so far in trials only) to image prostate cancer spread, because of the high specificity of PSMA expression on prostate cancer cells. Recent data show that PSMA-based imaging is significantly more sensitive in detecting metastatic prostate cancers than routine CT and bone scans.
A couple of other drugs in trials are perhaps worth mentioning: the investigational kinase inhibitor drug onvasertib was shown to improve responses to treatment with abiraterone (ZYTIGA), including in patients who were previously resistant to abiraterone. And there have been somewhat encouraging efficacy reports about a new chemotherapy drug called VERU-111.
New treatments for nmCRPC
Guidelines for treatment of CRPC that has not yet spread emphasize careful monitoring for possible development of metastases via imaging and measuring blood levels of a protein called prostate specific antigen (PSA), a marker of prostate cancer progression. PSA doubling time (PSADT), the amount of time it takes for PSA levels to double, is a good predictor of cancer progression. If PSADT is longer than 10 months, patients can continue to be observed and continue treatment with ADT. If PSADT is less than 10 months, patients should receive, in addition to the ongoing ADT, a drug that curbs androgen signaling, such as apalutamide, darolutamide, or enzalutamide to try and stave off development of metastases.
Of those three drugs, apalutamide (brand name Erleada) is a newer option. In the pivotal SPARTAN trial, the median metastasis-free survival time for nmCRPC patients who took apalutamide alongside standard ADT was 40.5 months, compared to 16.2 months for patients who received a placebo alongside ADT.
In short, there has been significant evolution in the development of new drugs to treat CRPC, especially mCRPC, and patients are encouraged to explore treatment options available in clinical trials. For more information on any of the treatments discussed in this article, and how to access them, I invite you to get support from Cancer Commons.
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